KR20200031088A - Gene mutations biomarker that predicts recurrence for prostate cancer - Google Patents
Gene mutations biomarker that predicts recurrence for prostate cancer Download PDFInfo
- Publication number
- KR20200031088A KR20200031088A KR1020200026257A KR20200026257A KR20200031088A KR 20200031088 A KR20200031088 A KR 20200031088A KR 1020200026257 A KR1020200026257 A KR 1020200026257A KR 20200026257 A KR20200026257 A KR 20200026257A KR 20200031088 A KR20200031088 A KR 20200031088A
- Authority
- KR
- South Korea
- Prior art keywords
- leu
- gly
- ala
- ser
- glu
- Prior art date
Links
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/118—Prognosis of disease development
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Abstract
Description
본 발명은 전립선암 환자의 예후 진단용 마커, 이를 포함하는 전립선암 환자의 예후 진단용 키트, 및 전립선암 환자의 예후 진단용 마커를 이용하여 전립선암의 예후 진단 및 치료 전략 결정을 위해 필요한 정보를 제공하는 방법에 관한 것이다.The present invention provides a method for providing prognostic diagnosis and treatment strategy for prostate cancer using a marker for prognostic diagnosis of a prostate cancer patient, a kit for prognostic diagnosis of a prostate cancer patient comprising the same, and a marker for prognostic diagnosis of a prostate cancer patient It is about.
전립선암의 정확한 원인은 밝혀지지 않았지만, 전립선암의 위험성을 증가시키는 몇 가지 인자로는 고령, 아프리카계 미국인 혈통, 가족력, 생활양식 요인(비만과 고지방 식사, 특히 동물 지방이 많은 식사)등을 들 수 있다. 전 세계 남성에서 두 번째로 흔히 진단되는 전립선암은 미국남성에서 1위, 한국남성에서 5위로 발생하며, 초기에 발견되는 국소 전립선암은 기대여명이 10년 이상이고, 완치 가능한 환자에서 표준치료로 수술적 전립선절제술(radical prostatectomy)을 시행하고 있다. 국소 전립선암의 치료에 로봇수술의 도입 등 수술 술기가 발달함에 따라 요실금, 성기능장애 등 수술 후 부작용은 감소하였지만 치료 후 재발의 위험은 상존한다. 전립선 암수술 치료 후 추적검사에서 전립선 특이항원(prostate-specific antigen, PSA)값이 측정 불가능한 수준으로 측정될 경우 잔여암이 없는 상태를 나타내는 것으로 생각되어 왔고 PSA값이 증가할 경우 잔여암 또는 재발암을 가장 먼저 나타내는 증거로 사용되어 왔다. 이 같은 PSA 상승은 생화학적 재발(biochemical recurrence, BCR)로 정의되며 5년 재발률이 23%, 10년 재발률이 35%, 15년 재발률이 44%로 보고되고 있다. 전립선암은 발병 후 종양 제거 시술로 인한 생존률은 높으나, 명확한 증상이 없이는 초기에 진단이 어렵다. 이러한 이유로 전립선암의 조기 진단과 암 발병 후 남은 수명을 체크할 수 있는 마커의 개발이 필요하다. 특허문헌 1에는 인간 전립선암의 검출 또는 진단에 사용되는 마커로서, 고병기 전립선암에서 CCM1 단백질의 항체를 이용하여 ELISA assay 방법으로 암전이를 예측하는 것을 특징으로 하는 CCM1 단백질의 항체를 포함하는 진단 바이오마커가 나와 있다. 전립선암을 비롯한 암을 진단하기 위한 마커가 개발되고 있으나, 전립선암 환자의 수술 후 예후까지 측정할 수 있는 마커, 특히 전립선암 환자의 재발과 특정 유전자의 돌연변이의 연관성에 대해서는 아직까지 자세한 연구가 이루어지지 않은 실정이다. 본 발명자는 전립선암의 재발을 진단하거나, 전립선암 환자에 대한 치료제를 발굴하여 치료 전략을 결정하기 위해서, 전립선암 환자의 예후를 진단할 수 있는 마커의 개발의 필요성에 착안하여 전립선암 환자에서 발견되는 유전자 변이와 재발 여부의 연관성에 대해서 연구하였다.Although the exact cause of prostate cancer is unknown, several factors that increase the risk of prostate cancer include older adults, African American lineage, family history, and lifestyle factors (obesity and high-fat diets, especially animal-fat diets). You can. Prostate cancer, the second most commonly diagnosed in men worldwide, occurs first in American men and fifth in Korean men. Local prostate cancer, which is found early, has a life expectancy of more than 10 years and is the standard treatment in patients who can be cured. Surgical prostatectomy is being performed. With the development of surgical techniques such as the introduction of robotic surgery in the treatment of local prostate cancer, postoperative side effects such as urinary incontinence and sexual dysfunction have decreased, but there is a risk of recurrence after treatment. When prostate-specific antigen (PSA) is measured at an unmeasurable level in follow-up after prostate cancer surgery treatment, it has been thought to indicate the absence of residual cancer. Has been used as the first evidence. This increase in PSA is defined as biochemical recurrence (BCR), with a 5-year recurrence rate of 23%, a 10-year recurrence rate of 35%, and a 15-year recurrence rate of 44%. Prostate cancer has a high survival rate due to tumor removal after onset, but it is difficult to diagnose early without clear symptoms. For this reason, early diagnosis of prostate cancer and development of a marker capable of checking the remaining life after the onset of cancer are needed.
전립선암 환자에 대한 적합한 치료적 전략을 적용하기 위해서는, 전립선암 환자의 예후를 예측하고 및 치료 전략 결정하는데 정보를 제공해 줄 수 있는 마커의 개발이 필요하다. 본 발명은 전립선암 환자의 재발 여부에 기반하여, 전립선암 환자의 예후 진단 및 치료 전략 결정에 도움을 주는 마커를 제공하는 것을 과제로 한다.In order to apply a suitable therapeutic strategy for prostate cancer patients, it is necessary to develop markers that can provide information to predict the prognosis of prostate cancer patients and to determine treatment strategies. An object of the present invention is to provide a marker that assists in the prognosis diagnosis and treatment strategy determination of a prostate cancer patient based on the recurrence of a prostate cancer patient.
상기의 목적을 달성하기 위하여, 본 발명의 핵심은 재발 특이적 마커를 검출할 수 있는 전립선암 환자의 재발 여부에 따른 전립선암 치료의 효과 차이의 예측 또는, 전립선암 환자의 예후 진단을 위해 필요한 정보를 제공하는 키트를 제공하며, 상기 재발 특이적 마커는 AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8로 이루어진 군으로부터 선택되는 적어도 하나를 암호화하는 유전자의 돌연변이다. 본 발명의 다른 측면은, 재발성 전립선암 환자의 샘플로부터 시료 DNA를 준비하는 단계; 상기 시료 DNA를 상기 키트를 이용하여 증폭하는 단계; 증폭 결과로부터 재발 특이적 마커의 유무를 확인하는 단계; 재발 특이적 마커가 확인된 전립선암 환자에 임의의 전립선암 치료 후보 물질을 처리하거나, 임의의 방법으로 치료하는 단계; 및 임의의 전립선암 치료 후보 물질 또는 임의의 치료 방법이 전립선암을 개선하거나, 치료할 경우 재발 특이적 마커가 확인된 재발성 전립선암 환자에 적합한 치료 후보 물질 또는 치료 방법으로 채택하는 단계;를 포함하는 전립선암 환자의 재발 여부에 따른 전립선암 치료 효과의 차이를 판정하기 위해 필요한 정보를 제공하는 방법을 제공한다. 본 발명의 다른 측면은 전립선암 환자의 샘플로부터 시료 DNA를 준비하는 단계; 상기 시료 DNA를 청구항 1의 키트를 이용하여 증폭하는 단계; 및 상기 증폭 결과로부터 재발 특이적 마커의 유무를 확인하는 단계;를 포함하는 전립선암 환자의 재발에 따른 전립선암의 예후 진단을 위해 필요한 정보를 제공하는 방법을 제공한다.In order to achieve the above object, the core of the present invention is the prediction of the difference in the effectiveness of prostate cancer treatment according to whether or not the recurrence of a prostate cancer patient capable of detecting a recurrence specific marker, or information necessary for prognostic diagnosis of a prostate cancer patient Provided kit, wherein the recurrence specific marker is AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8 It is a mutation in the gene that codes for one. Another aspect of the present invention, preparing a sample DNA from a sample of a patient with recurrent prostate cancer; Amplifying the sample DNA using the kit; Confirming the presence or absence of a recurrence specific marker from the amplification result; Treating a prostate cancer candidate for treatment with any prostate cancer treatment candidate material, or by any method; And adopting any prostate cancer treatment candidate substance or any treatment method as a treatment candidate substance or treatment method suitable for a recurrent prostate cancer patient in which a recurrence specific marker is identified when improving or treating prostate cancer. Provides a method for providing information necessary to determine a difference in a prostate cancer treatment effect according to whether a prostate cancer patient recurs. Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a patient with prostate cancer; Amplifying the sample DNA using the kit of
본 발명에서 발굴한 돌연변이 유전자인, AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자의 돌연변이와 전립선암 환자의 재발이 연관성이 있으므로, 상기 유전자의 돌연변이 여부를 확인함으로써 전립선암 환자의 재발에 따른 전립선암 치료 효과의 차이 및 생존률 차이를 예측할 수 있다. 아울러, 본 발명에서 발굴한 돌연변이 유전자인 AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8로 구성된 유전자 군에서 선택되는 하나의 유전자의 돌연변이와, 재발성 전립선암 환자의 생존율, 또는 상기 유전자의 변이와 전립선암의 재발율이 각각 연관성이 있으므로, 전립선암 환자의 예후를 예측하는데 본 발명의 유전자들의 돌연변이를 마커로서 사용할 수 있다. 다만, 본 발명의 효과는 상기에서 언급한 효과로 제한되지 아니하며, 언급되지 않은 또 다른 효과들은 하기의 기재로부터 본 기술 분야의 통상의 기술자에게 명확히 이해될 수 있을 것이다.Of at least one gene selected from the gene group consisting of the mutation genes found in the present invention, AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8 Since mutation and recurrence of a patient with prostate cancer are related, it is possible to predict a difference in a treatment effect and a survival rate according to the recurrence of a patient with prostate cancer by confirming whether the gene is mutated. In addition, one of the genes selected from the gene group consisting of the mutation genes found in the present invention AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8 Mutations and mutations of the genes of the present invention can be used as markers to predict the prognosis of a prostate cancer patient, since the survival rate of a patient with recurrent prostate cancer, or the mutation rate of the gene and the recurrence rate of prostate cancer are each related. However, the effects of the present invention are not limited to the above-mentioned effects, and other effects not mentioned will be clearly understood by those skilled in the art from the following description.
도 1 내지 도 16에 AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8 각각의 유전자에 대해서, 해당 유전자에 돌연변이가 있는 전립선암 환자(적색)와 해당 유전자에 돌연변이가 없는 전립선암 환자(청색)의 총 생존 기간 또는 무병 생존 기간에 관한 그래프와 유전자 네트워크 그림이다.For each of the genes AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8 in FIGS. 1 to 16, prostate cancer patients with mutations in the gene (Red) and graphs and genetic network diagrams for the total or disease-free survival of prostate cancer patients (blue) with no mutations in the gene.
본 명세서에 있어서, 달리 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야의 통상의 기술자에 의해 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로, 본 명세서에서 사용된 명명법 및 이하에 기술하는 실험 방법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다. 이하, 본 발명을 상세히 설명한다.In this specification, unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person skilled in the art to which the present invention pertains. In general, the nomenclature used herein and the experimental methods described below are well known and commonly used in the art. Hereinafter, the present invention will be described in detail.
1. 전립선암 환자에서 재발 특이적 돌연변이 유전자, 및 이들 돌연변이 유전자를 검출할 수 있는 프라이머 세트1. A set of recurrent specific mutant genes and primers capable of detecting these mutant genes in patients with prostate cancer
본 발명의 일 측면은 AGXT2(Gene bank accession number: NM_031900.3), ATG2A(Gene bank accession number: NM_015104.2), ATP13A5(Gene bank accession number: NM_198505.2), CD207(Gene bank accession number: NM_015717.4), COL21A1(Gene bank accession number: NM_030820.3), CPXM1(Gene bank accession number: NM_019609.4), CS(Gene bank accession number: NM_004077.2), CTSE(Gene bank accession number: NM_001910.3), FCRL1(Gene bank accession number: NM_052938.4), LINGO1(Gene bank accession number: NM_032808.6), MYH11(Gene bank accession number: NM_002474.2), PLIN3(Gene bank accession number: NM_005817.4), POLR2B(Gene bank accession number: NM_000938.2), SERINC3(Gene bank accession number: NM_006811.3) 및 SLC38A8(Gene bank accession number: NM_001080442.2)로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자의 돌연변이를 검출할 수 있는 전립선암의 예후 진단용 키트를 제공한다. 본 발명의 한 구현 예에서, 하기의 유전자의 돌연변이 중에서 선택되는 적어도 하나의 유전자의 돌연변이를 검출할 수 있는 전립선암의 예후 진단용 키트를 제공한다:One aspect of the present invention, AGXT2 (Gene bank accession number: NM_031900.3), ATG2A (Gene bank accession number: NM_015104.2), ATP13A5 (Gene bank accession number: NM_198505.2), CD207 (Gene bank accession number: NM_015717 .4), COL21A1 (Gene bank accession number: NM_030820.3), CPXM1 (Gene bank accession number: NM_019609.4), CS (Gene bank accession number: NM_004077.2), CTSE (Gene bank accession number: NM_001910.3 ), FCRL1 (Gene bank accession number: NM_052938.4), LINGO1 (Gene bank accession number: NM_032808.6), MYH11 (Gene bank accession number: NM_002474.2), PLIN3 (Gene bank accession number: NM_005817.4), Detect mutation of at least one gene selected from the gene group consisting of Gene bank accession number: POLR2B (NM_000938.2), Gene bank accession number: SERINC3 (NM_006811.3), and Gene bank accession number: NM_001080442.2 (SLC38A8) Provided is a kit for prognostic diagnosis of prostate cancer. In one embodiment of the present invention, there is provided a kit for prognostic diagnosis of prostate cancer capable of detecting mutations in at least one gene selected from mutations in the following genes:
서열번호 1의 아미노산 서열로 나타내는 AGXT2를 암호화하는 유전자의 돌연변이, 서열번호 2의 아미노산 서열로 나타내는 ATG2A를 암호화하는 유전자의 돌연변이, 서열번호 3의 아미노산 서열로 나타내는 ATP13A5를 암호화하는 유전자의 돌연변이, 서열번호 4의 아미노산 서열로 나타내는 CD207를 암호화하는 유전자의 돌연변이, 서열번호 5의 아미노산 서열로 나타내는 COL21A1를 암호화하는 유전자의 돌연변이, 서열번호 6의 아미노산 서열로 나타내는 CPXM1를 암호화하는 유전자의 돌연변이, 서열번호 7의 아미노산 서열로 나타내는 CS를 암호화하는 유전자의 돌연변이, 서열번호 8의 아미노산 서열로 나타내는 CTSE를 암호화하는 유전자의 돌연변이, 서열번호 9의 아미노산 서열로 나타내는 FCRL1를 암호화하는 유전자의 돌연변이, 서열번호 10의 아미노산 서열로 나타내는 LINGO1를 암호화하는 유전자의 돌연변이, 서열번호 11의 아미노산 서열로 나타내는 MYH11를 암호화하는 유전자의 돌연변이, 서열번호 12의 아미노산 서열로 나타내는 PLIN3를 암호화하는 유전자의 돌연변이, 서열번호 13의 아미노산 서열로 나타내는 POLR2B를 암호화하는 유전자의 돌연변이, 서열번호 14의 아미노산 서열로 나타내는 SERINC3를 암호화하는 유전자의 돌연변이, 서열번호 15의 아미노산 서열로 나타내는 SLC38A8를 암호화하는 유전자의 돌연변이 본 발명에서 용어,‘진단'은 병리 상태의 존재 또는 특징을 확인하는 것으로서, 본 발명의 목적상, 암의 발병 여부를 확인하는 것뿐만 아니라 암의 치료 후 해당 개체의 재발, 전이, 약물 반응성, 내성 등과 같은 여부를 판단하는 것을 의미한다. 바람직하게 본 발명의 유전자의 돌연변이를 이용하는 경우, 개체의 시료로부터 돌연변이 여부를 확인함으로써 해당 개체의 암의 발병 여부뿐만 아니라, 향후 해당 개체의 예후가 좋을 것인지 여부에 대해서까지 예측이 가능하다. 본 발명에서 용어 ‘예후’란 암과 같은 신생물 질환의 예를 들어 재발, 전이성 확산 및 약물 내성을 비롯한 암-기인성 사망 또는 진행의 가능성 등의 병의 경과 및 완치 여부를 의미한다. 본 발명의 목적상 전립선암의 예후를 예측하는 것일 수 있으며, 바람직하게는 전립선암 환자의 무병생존율 또는 생존율을 예측하는 것이다. 본 발명에서 용어 ‘암’은 이상 세포의 조절되지 않는 성장을 특징으로 하는 질환 부류의 임의의 일원을 포함한다. 상기 용어는, 악성, 양성, 연조직 또는 고형 중 어느 것으로 특징지어지든, 모든 알려진 암 및 신생물 상태, 및 전이 전/후의 암을 포함하는 모든 시기 및 등급의 암을 포함한다. 본 발명에서 용어 ‘유전자’ 및 이의 변형물은 폴리펩티드 사슬 생성에 관여한 DNA 조각을 포함하며; 이는 코딩 부위 이전 및 이후의 부위, 예를 들면 프로모터 및 3'-미번역 부위를 각각 포함할 뿐 아니라, 개별적인 코딩 단편(엑손) 사이의 개입 서열(인트론)을 포함한다. 상기 유전자의 돌연변이는 임의의 하나 이상의 돌연변이를 포함할 수 있고, 예를 들면, 절단형(truncating) 돌연변이, 미스센스(missense) 돌연변이(또는 과오 돌연변이), 넌센스(nonsense) 돌연변이, 프레임 시프트(frame shift) 돌연변이, 인프레임(in-frame) 돌연변이(또는 해독틀내 돌연변이), 스플라이스 돌연변이 및 스플라이스 사이트(splice_region) 돌연변이로 이루어진 군으로부터 선택되는 적어도 하나의 돌연변이를 가질 수 있다. 상기 프레임 시프트 돌연변이는 프레임 시프트 삽입(frame shift insert, FS ins) 돌연변이 및 프레임 시프트 결실 돌연변이(frame shift delete, FS del) 중 적어도 하나일 수 있다. 상기 인-프레임 돌연변이는 인-프레임 삽입(in-frame insertion, IF ins) 돌연변이 및 인-프레임 결실(in-frame delete, IF del) 돌연변이 중 적어도 하나일 수 있다. 폴리펩티드 서열에서의 돌연변이와 관련하여 용어 "X#Y"는 본 기술 분야에서 자명하게 인식되는 것으로, 여기서 "#"은 폴리펩티드의 아미노산 번호와 관련하여 돌연변이 위치를 나타내고, "X"는 야생형 아미노산 서열의 그 위치에서 발견되는 아미노산을 나타내며, "Y"는 그 위치에서의 돌연변이체 아미노산을 나타낸다. 예를 들어, AGXT2 폴리펩티드와 관련하여 표기 "T79M"는 야생형 AGXT2 서열의 아미노산 번호 79에는 트레오닌이 존재하고, 트레오닌이 돌연변이체 AGXT2 서열에서 메티오닌으로 대체되었음을 나타낸다. 상기 유전자들의 돌연변이는 하기와 같다. Mutation of gene encoding AGXT2 represented by amino acid sequence of SEQ ID NO: 1, mutation of gene encoding ATG2A represented by amino acid sequence of SEQ ID NO: 2, mutation of gene encoding ATP13A5 represented by amino acid sequence of SEQ ID NO: 3, SEQ ID NO: Mutation of gene encoding CD207 represented by amino acid sequence of 4, mutation of gene encoding COL21A1 represented by amino acid sequence of SEQ ID NO: 5, mutation of gene encoding CPXM1 represented by amino acid sequence of SEQ ID NO: 6, SEQ ID NO: 7 Mutation of gene encoding CS represented by amino acid sequence, mutation of gene encoding CTSE represented by amino acid sequence of SEQ ID NO: 8, mutation of gene encoding FCRL1 represented by amino acid sequence of SEQ ID NO: 9, amino acid sequence of SEQ ID NO: 10 As i The mutation of the gene encoding LINGO1, the mutation of the gene encoding MYH11 represented by the amino acid sequence of SEQ ID NO: 11, the mutation of the gene encoding PLIN3 represented by the amino acid sequence of SEQ ID NO: 12, POLR2B represented by the amino acid sequence of SEQ ID NO: 13 Mutation of the gene encoding SERINC3 represented by the amino acid sequence of SEQ ID NO: 14, mutation of the gene encoding SLC38A8 represented by the amino acid sequence of SEQ ID NO: 15 In the present invention, the term 'diagnosis' is a pathological condition. By confirming the existence or characteristics, for the purpose of the present invention, it means not only to determine whether or not the cancer has occurred, but also to determine whether the subject has recurrence, metastasis, drug reactivity, resistance, etc. after treatment of the cancer. Preferably, when the mutation of the gene of the present invention is used, it is possible to predict whether the subject has a good prognosis as well as whether the subject has a cancer by confirming whether or not the subject has a mutation. In the present invention, the term 'prognosis' refers to whether the disease progresses or is cured, such as the possibility of cancer-induced death or progression, including, for example, relapse, metastatic spread, and drug resistance, for example, a neoplastic disease such as cancer. For the purposes of the present invention, it may be to predict the prognosis of prostate cancer, preferably to predict the disease-free survival rate or survival rate of prostate cancer patients. The term 'cancer' in the present invention includes any member of the class of diseases characterized by unregulated growth of abnormal cells. The term includes all known cancer and neoplastic conditions, whether characterized as malignant, benign, soft tissue, or solid, and all stages and grades of cancer, including cancer before and after metastasis. The term “gene” and variations thereof in the present invention includes DNA fragments involved in polypeptide chain production; It includes sites before and after the coding site, such as a promoter and a 3'-untranslated site, respectively, as well as intervening sequences (introns) between individual coding fragments (exons). Mutations in the gene may include any one or more mutations, for example, truncating mutations, missense mutations (or mistaken mutations), nonsense mutations, frame shifts ) Mutations, in-frame mutations (or in-frame mutations), splice mutations and splice site (splice_region) mutations. The frame shift mutation may be at least one of a frame shift insert (FS ins) mutation and a frame shift delete (FS del) mutation. The in-frame mutation may be at least one of an in-frame insertion (IF ins) mutation and an in-frame delete (IF del) mutation. The term "X # Y" with respect to mutations in the polypeptide sequence is apparently recognized in the art, where "#" refers to the position of the mutation in relation to the amino acid number of the polypeptide, and "X" of the wild-type amino acid sequence. The amino acid found at that position, "Y" indicates the mutant amino acid at that position. For example, in the context of the AGXT2 polypeptide, the notation “T79M” indicates that threonine was present at amino acid number 79 of the wild-type AGXT2 sequence, and that threonine was replaced by methionine in the mutant AGXT2 sequence. Mutations of the genes are as follows.
서열번호 1로 나타내는 AGXT2의 아미노산 서열에서, T79M 및 E366Q로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 2로 나타내는 ATG2A의 아미노산 서열에서, R553Q, C1270Y, F472S, R559C로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 3으로 나타내는 ATP13A5의 아미노산 서열에서, P389L, A34V, S1041I, T686I, R27Q, 및L144M로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 4로 나타내는 CD207의 아미노산 서열에서, D269G로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 넌센스 돌연변이에서 *는 해당 아미노산 위치에서의 아미노산 합성이 종료된 것을 나타낸다(이하에서는 설명을 생략함); R321* 적어도 하나인 넌센스 돌연변이; 서열번호 5로 나타내는 COL21A1의 아미노산 서열에서, A224S, T323S, T651I, 및 G707V로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 6로 나타내는 CPXM1의 아미노산 서열에서, R662H 및 L726P로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 7로 나타내는 CS의 아미노산 서열에서, K34R 및 L389V 중 적어도 하나인 미스센스 돌연변이고, R356* 중 적어도 하나인 넌센스 돌연변이;In the amino acid sequence of AGXT2 shown in SEQ ID NO: 1, at least one of the missense mutations selected from the group consisting of T79M and E366Q; In the amino acid sequence of ATG2A shown in SEQ ID NO: 2, at least one of the missense mutation selected from the group consisting of R553Q, C1270Y, F472S, R559C; In the amino acid sequence of ATP13A5 shown in SEQ ID NO: 3, at least one missense mutation selected from the group consisting of P389L, A34V, S1041I, T686I, R27Q, and L144M; In the amino acid sequence of CD207 shown in SEQ ID NO: 4, at least one selected from the group consisting of D269G is a missense mutation; * In the nonsense mutation indicates that the amino acid synthesis at the corresponding amino acid position has been completed (the description is omitted below); R321 * at least one nonsense mutation; In the amino acid sequence of COL21A1 as shown in SEQ ID NO: 5, at least one missense mutation selected from the group consisting of A224S, T323S, T651I, and G707V; In the amino acid sequence of CPXM1 shown in SEQ ID NO: 6, at least one selected from the group consisting of R662H and L726P missense mutation; In the amino acid sequence of CS represented by SEQ ID NO: 7, a missense mutation that is at least one of K34R and L389V, and a nonsense mutation that is at least one of R356 *;
서열번호 8로 나타내는 CTSE의 아미노산 서열에서, T116M 및 P30L로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 9로 나타내는 FCRL1의 아미노산 서열에서, A74T, A284S, 및 A320V 로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 10로 나타내는 LINGO1의 아미노산 서열에서, F410I, A9V, V138I 및 P549H로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 11로 나타내는 MYH11의 아미노산 서열에서, A815T, E1888K, T975M, A732V, A1259V 및 A334V로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이고, R1609* 적어도 하나인 넌센스 돌연변이; 서열번호 12로 나타내는 PLIN3의 아미노산 서열에서, 프레임 시프트 돌연변이의 표기 방식은, 아미노산 종류(아미노산 위치)아미노산 종류fs*(아미노산 위치에서 하류 방향으로 정지 코돈까지의 뉴클레오티드 개수)이다. (프레임 시프트 삽입 돌연변이, 프레임 시프트 결실 돌연변이 모두 동일한 표기 방식이며, 이하에서는 설명을 생략함) Q263Rfs*14 및 Q174Lfs*48 중 적어도 하나인 프레임 시프트 결실(frame shift delete, FS del) 돌연변이고, A119V중 적어도 하나인 미스센스 돌연변이; 서열번호 13로 나타내는 POLR2B의 아미노산 서열에서, D45Y, R157W 및 Q948R로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 14로 나타내는 SERINC3의 아미노산 서열에서, I45S 및 D88V로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 15로 나타내는 SLC38A8의 아미노산 서열에서, V193M 및 V61M로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 상기 유전자의 돌연변이를 이용하여 전립선암의 예후를 진단하기 위한 분석 방법으로 RT-PCR, 직접 핵산 서열분석 방법, 마이크로 어레이가 사용될 수 있으며, 본 발명의 유전자의 돌연변이를 이용하여 돌연변이의 존재를 확인할 수 있는 방법이라면 제한없이 적용할 수 있다. In the amino acid sequence of CTSE represented by SEQ ID NO: 8, at least one selected from the group consisting of T116M and P30L, a missense mutation; In the amino acid sequence of FCRL1 shown in SEQ ID NO: 9, at least one of the missense mutations selected from the group consisting of A74T, A284S, and A320V; In the amino acid sequence of LINGO1 shown in SEQ ID NO: 10, at least one missense mutation selected from the group consisting of F410I, A9V, V138I and P549H; In the amino acid sequence of MYH11 shown in SEQ ID NO: 11, at least one of the missense mutations selected from the group consisting of A815T, E1888K, T975M, A732V, A1259V and A334V, and R1609 * at least one nonsense mutation; In the amino acid sequence of PLIN3 shown in SEQ ID NO: 12, the notation method of the frame shift mutation is amino acid type (amino acid position) amino acid type fs * (number of nucleotides from amino acid position to stop codon in the downstream direction). (Frame shift insertion mutation, frame shift deletion mutation are all the same notation method, and description will be omitted below) Frame shift delete (FS del) mutation, which is at least one of Q263Rfs * 14 and Q174Lfs * 48, among A119V At least one missense mutation; In the amino acid sequence of POLR2B shown in SEQ ID NO: 13, at least one missense mutation selected from the group consisting of D45Y, R157W and Q948R; In the amino acid sequence of SERINC3 shown in SEQ ID NO: 14, at least one selected from the group consisting of I45S and D88V is a missense mutation; In the amino acid sequence of SLC38A8 shown in SEQ ID NO: 15, at least one missense mutation selected from the group consisting of V193M and V61M; RT-PCR, a direct nucleic acid sequencing method, and microarray may be used as an analysis method for diagnosing the prognosis of prostate cancer using the mutation of the gene, and the presence of the mutation may be confirmed using the mutation of the gene of the present invention. Any method can be applied without limitation.
한 실시 양태에서, 돌연변이의 존재는 엄격한 조건 하에 각 유전자의 돌연변이의 폴리뉴클레오티드에 혼성화하는 항-(각 유전자의 돌연변이) 항체 또는 핵산 프로브를 사용하여 결정된다. 또 다른 실시양태에서, 항체 또는 핵산 프로브는 검출가능하게 표지된다. 또 다른 실시양태에서, 표지는 면역형광 표지, 화학발광 표지, 인광 표지, 효소 표지, 방사성 표지, 아비딘/비오틴, 콜로이드성 금 입자, 착색 입자 및 자기 입자로 이루어진 군으로부터 선택된다. 또 다른 실시양태에서, 돌연변이의 존재는 방사성면역 검정, 웨스턴블롯 검정, 면역형광 검정, 효소면역 검정, 면역침전 검정, 화학발광 검정, 면역조직화학 검정, 도트 블롯 검정, 슬롯 블롯 검정 또는 유동 세포측정 검정에 의해 결정된다. 또 다른 실시양태에서, 돌연변이의 존재는 RT-PCR에 의해 결정된다. 또 다른 실시양태에서, 돌연변이의 존재는 핵산 서열분석에 의해 결정된다. 본 발명에서 용어 ‘폴리뉴클레오티드’는 일반적으로 비변형된 RNA 또는 DNA 또는 변형된 RNA 또는 DNA일 수 있는 임의의 폴리리보뉴클레오티드 또는 폴리데옥시리보뉴클레오티드를 지칭한다. 따라서, 예를 들어 기존에 정의된 바와 같은 폴리뉴클레오티드는 비제한적으로 단일- 및 이중-가닥 DNA, 단일- 및 이중-가닥 영역을 포함하는 DNA, 단일- 및 이중-가닥 RNA, 및 단일- 및 이중-가닥 영역을 포함하는 RNA, 단일-가닥 또는 보다 전형적으로는 이중-가닥일 수도 있거나 또는 단일- 및 이중-가닥 영역을 포함할 수 있는 DNA 및 RNA를 포함하는 하이브리드 분자를 포함한다. 따라서, 안정성 또는 다른 이유로 인해 변형된 백본을 갖는 DNA 또는 RNA는 기존에 의도된 용어와 같은 ‘폴리뉴클레오티드’이다. 또한, 이노신과 같은 비통상적 염기 또는 삼중수소화 염기와 같은 변형된 염기를 포함하는 DNA 또는 RNA가 기존에 정의된 바와 같은 용어 ‘폴리뉴클레오티드’에 포함된다. 일반적으로, 용어 ‘폴리뉴클레오티드’는 비변형된 폴리뉴클레오티드의 모든 화학적으로, 효소적으로 및/또는 대사적으로 변형된 형태를 포함한다. 폴리뉴클레오티드는 시험관내 재조합 DNA-매개 기술을 비롯한 다양한 방법에 의해, 그리고 세포 및 유기체 내의 DNA의 발현에 의해 제조될 수 있다.In one embodiment, the presence of a mutation is determined using an anti- (mutation of each gene) antibody or nucleic acid probe that hybridizes to the polynucleotide of the mutation of each gene under stringent conditions. In another embodiment, the antibody or nucleic acid probe is detectably labeled. In another embodiment, the label is selected from the group consisting of immunofluorescent labels, chemiluminescent labels, phosphorescent labels, enzyme labels, radioactive labels, avidin / biotin, colloidal gold particles, colored particles and magnetic particles. In another embodiment, the presence of the mutation is a radioimmunoassay, western blot assay, immunofluorescence assay, enzymatic immunoassay, immunoprecipitation assay, chemiluminescence assay, immunohistochemistry assay, dot blot assay, slot blot assay or flow cytometry. Determined by assay. In another embodiment, the presence of the mutation is determined by RT-PCR. In another embodiment, the presence of the mutation is determined by nucleic acid sequencing. The term “polynucleotide” in the present invention generally refers to any polyribonucleotide or polydeoxyribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. Thus, for example, polynucleotides as previously defined include, but are not limited to, single- and double-stranded DNA, DNA comprising single- and double-stranded regions, single- and double-stranded RNA, and single- and double-stranded -Hybrid molecules comprising RNA and RNA comprising a strand region, single-stranded or more typically double-stranded or DNA and RNA, which may include single- and double-stranded regions. Thus, DNA or RNA with a backbone modified for stability or other reasons is a 'polynucleotide' as the term previously intended. In addition, DNA or RNA comprising a non-conventional base such as inosine or a modified base such as a tritium base is included in the term 'polynucleotide' as previously defined. In general, the term 'polynucleotide' includes all chemically, enzymatically and / or metabolically modified forms of unmodified polynucleotides. Polynucleotides can be prepared by a variety of methods, including in vitro recombinant DNA-mediated technology, and by expression of DNA in cells and organisms.
상기 돌연변이를 검출할 수 있는, 즉 전립선암의 재발 예후 진단용 프라이머 세트는 하기와 같다. AGXT2의 돌연변이 검출을 위한 서열번호 16을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; ATG2A의 돌연변이 검출을 위한 서열번호 17을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; ATP13A5의 돌연변이 검출을 위한 서열번호 18을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; CD207의 돌연변이 검출을 위한 서열번호 19을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; COL21A1의 돌연변이 검출을 위한 서열번호 20을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; CPXM1의 돌연변이 검출을 위한 서열번호 21을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; CS의 돌연변이 검출을 위한 서열번호 22를 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; CTSE의 돌연변이 검출을 위한 서열번호 23을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; FCRL1의 돌연변이 검출을 위한 서열번호 24를 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; LINGO1의 돌연변이 검출을 위한 서열번호 25을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; MYH11의 돌연변이 검출을 위한 서열번호 26을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; PLIN3의 돌연변이 검출을 위한 서열번호 27을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; POLR2B의 돌연변이 검출을 위한 서열번호 28을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; SERINC3의 돌연변이 검출을 위한 서열번호 29를 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; SLC38A8의 돌연변이 검출을 위한 서열번호 30을 나타내는 염기서열 쌍으로 이루어진 군으로부터 선택된 적어도 하나의 프라이머 세트; The set of primers for detecting the mutation, that is, diagnosing prognosis for recurrence of prostate cancer is as follows. At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 16 for mutation detection of AGXT2; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 17 for mutation detection of ATG2A; At least one primer set selected from the group consisting of a nucleotide sequence pair showing SEQ ID NO: 18 for mutation detection of ATP13A5; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 19 for mutation detection of CD207; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 20 for mutation detection of COL21A1; At least one primer set selected from the group consisting of a nucleotide sequence pair showing SEQ ID NO: 21 for mutation detection of CPXM1; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 22 for mutation detection of CS; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 23 for mutation detection of CTSE; At least one primer set selected from the group consisting of a nucleotide sequence pair as shown in SEQ ID NO: 24 for mutation detection of FCRL1; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 25 for mutation detection of LINGO1; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 26 for mutation detection of MYH11; At least one primer set selected from the group consisting of a nucleotide sequence pair showing SEQ ID NO: 27 for mutation detection of PLIN3; At least one primer set selected from the group consisting of a nucleotide sequence pair showing SEQ ID NO: 28 for mutation detection of POLR2B; At least one primer set selected from the group consisting of a nucleotide sequence pair as shown in SEQ ID NO: 29 for mutation detection of SERINC3; At least one primer set selected from the group consisting of a base sequence pair showing SEQ ID NO: 30 for mutation detection of SLC38A8;
상기와 같이 제작된 본 발명의 키트는 기존의 일반적인 유전자의 돌연변이 검색 방법에 비하여 시간과 비용이 절감되어 매우 경제적이다. SSCP(Single Strand Conformational Polymorphism), PTT(Protein Truncation Test), 클로닝(cloning), 직접 염기서열 분석(direct sequencing) 등과 같은 기존의 유전자 돌연변이 검색 방법을 이용하여 한 유전자를 모두 검사하려면 평균적으로 수 일 내지 수개월이 소요된다. 또한, 차세대 염기서열분석법(next generation sequencing: NGS)을 통해서 유전자의 돌연변이를 검사할 수 있지만 비용이 높다는 문제점이 있었다. 돌연변이를 SSCP, 클로닝, 직접 염기 서열 분석, RFLP (Restriction Fragment Length Polymorphism) 등의 기존 분석방법에 의해 검사하는 경우 검사 완료까지 약 한달 가량이 소요되는 반면, 본 발명의 키트를 이용하면 시료 DNA가 준비되어 있을 경우 약 10 내지 11시간 내에 결과를 얻을 수 있고, 칩 하나에 돌연변이를 검출할 수 있는 프라이머 세트가 함께 집적되어 있기 때문에 기존의 방법에 비해 시간뿐만 아니라 비용까지 절감할 수 있다. 기존의 방법에 비해 매 실험 당 평균 절반 이하의 시약비가 소모되므로 연구자의 인건비까지 감안하였을 때 더욱 큰 비용의 절감 효과를 기대할 수 있게 된다.The kit of the present invention manufactured as described above is very economical because it saves time and cost compared to a conventional method for searching for mutations in general genes. In order to test all genes using conventional gene mutation detection methods such as Single Strand Conformational Polymorphism (SSCP), Protein Truncation Test (PTT), cloning, and direct sequencing, on average, several days to several days It takes several months. In addition, although mutation of a gene can be tested through next generation sequencing (NGS), there is a problem that the cost is high. When the mutation is tested by conventional analysis methods such as SSCP, cloning, direct sequencing, and RFLP (Restriction Fragment Length Polymorphism), it takes about a month to complete the test, while using the kit of the present invention, sample DNA is prepared If possible, results can be obtained within about 10 to 11 hours, and since a set of primers capable of detecting mutations are integrated together on one chip, not only time but cost can be reduced compared to the conventional method. Compared to the conventional method, less than half the reagent cost is consumed per experiment, so considering the labor cost of the researcher, it is possible to expect a greater cost reduction effect.
2. 재발 특이적 돌연변이 유전자를 이용한 전립선암의 예후 진단을 위해 필요한 정보를 제공하는 방법2. Method of providing information necessary for prognostic diagnosis of prostate cancer using recurrent specific mutant gene
본 발명의 다른 측면은 전립선암 환자의 샘플로부터 시료 DNA를 준비하는 단계; 상기 시료 DNA를 청구항 1의 전립선암의 예후 진단용 키트를 이용하여 증폭하는 단계; 및 상기 증폭 결과로부터 돌연변이 유무를 확인하는 단계;를 포함하는 전립선암의 예후 진단을 위해 필요한 정보를 제공하는 방법을 제공한다. Another aspect of the present invention comprises the steps of preparing a sample DNA from a sample of a patient with prostate cancer; Amplifying the sample DNA using a kit for prognostic diagnosis of prostate cancer of
상기‘전립선암의 예후 진단용 키트’에 대한 설명은 ‘ 1. 전립선암 환자에서 재발 특이적 돌연변이 유전자 및 이들 돌연변이 유전자를 검출할 수 있는 프라이머 세트 ’에 기재한 바와 동일하므로 구체적인 설명을 생략한다.The description of the 'kit for prognostic diagnosis of prostate cancer' is the same as described in ' 1. A set of primers capable of detecting recurrent specific mutant genes and these mutant genes in prostate cancer patients ', and thus detailed description thereof will be omitted.
기존에 사용되는 용어 ‘샘플'은 환자로부터 수득한 임의의 생물학적 표본을 포함한다. 샘플은 전혈, 혈장, 혈청, 적혈구, 백혈구(예를 들어 말초 혈액 단핵구), 유관액, 복수, 늑막 유출물(pleural efflux), 수유관액(nipple aspirate), 림프액(예를 들어 림프절의 파종성 종양 세포), 골수 흡인물, 타액, 소변, 대변(즉, 배설물), 가래, 기관지 세척액, 눈물, 미세 바늘 흡인물(예를 들어 무작위 유선 미세 바늘 흡인에 의해 수확된), 임의의 기타 체액, 조직 샘플(예를 들어 종양 조직) 예컨대 종양 생검(예를 들어 천자 생검) 또는 림프절(예를 들어 감시 (sentinel) 림프절 생검), 조직 샘플(예를 들어 종양 조직), 예를 들면 종양의 수술적 절제, 및 이의 세포 추출물을 포함한다. 일부 구현예에서, 샘플은 전혈 또는 이의 일부 성분, 예를 들면 혈장, 혈청 또는 세포 펠렛이다. 다른 구현예에서, 샘플은 당업계에 공지된 임의의 기법을 사용하여 전혈 또는 이의 세포 분획물로부터 고형 종양의 순환 세포를 단리함으로써 수득된다. 다른 구현예에서, 샘플은 예를 들어 대장암과 같은 고형 종양으로부터의 포르말린 고정된 파라핀 포매 (FFPE) 종양 조직 샘플이다. 특정 구현예에서, 샘플은 대장암을 갖는 대상으로부터 수득한 동결 조직으로부터 제조된 종양 용해물 또는 추출물이다. 용어 ‘환자’는 통상 인간을 포함할 뿐 아니라 다른 동물, 예를 들어 다른 영장류, 설치류, 개, 고양이, 말, 양, 돼지 등을 포함할 수 있다. 상기 방법은 전립선암 환자의 총 생존율 또는 무병 생존율을 예측할 수 있다.The term 'sample', as used previously, includes any biological sample obtained from a patient. Samples include whole blood, plasma, serum, red blood cells, white blood cells (e.g. peripheral blood monocytes), mammary fluid, ascites, pleural efflux, nipple aspirate, lymphatic fluid (e.g., disseminated tumors of lymph nodes) Cells), bone marrow aspirates, saliva, urine, feces (i.e., feces), sputum, bronchial lavage fluid, tears, microneedle aspirates (e.g. harvested by random mammary microneedle aspiration), any other bodily fluid, tissue Surgical excision of a sample (eg tumor tissue) such as a tumor biopsy (eg puncture biopsy) or lymph node (eg a sentinel lymph node biopsy), a tissue sample (eg tumor tissue), eg tumor , And cell extracts thereof. In some embodiments, the sample is whole blood or some components thereof, such as plasma, serum or cell pellets. In another embodiment, a sample is obtained by isolating circulating cells of a solid tumor from whole blood or cell fractions thereof using any technique known in the art. In other embodiments, the sample is a formalin fixed paraffin embedded (FFPE) tumor tissue sample from a solid tumor, such as colorectal cancer. In certain embodiments, the sample is a tumor lysate or extract prepared from frozen tissue obtained from a subject with colorectal cancer. The term 'patient' usually includes humans as well as other animals, such as other primates, rodents, dogs, cats, horses, sheep, pigs, and the like. The method can predict the total survival rate or disease-free survival rate of patients with prostate cancer.
본 발명에서 용어 ‘총 생존율(overall survival)’은 질환, 예컨대 암으로 진단되거나 그에 대해 치료된 후 한정된 시간 동안 살아 있는 환자를 기재하는 임상적 종점을 포함하며, 암의 재발 여부에 관계 없이 생존하는 가능성을 의미한다.The term 'overall survival' in the present invention includes a clinical endpoint that describes a patient who is alive for a limited period of time after being diagnosed or treated for a disease, such as cancer, and survives regardless of whether the cancer has recurred or not. It means possibility.
본 발명에서 용어 ‘무병생존율(disease-free survival, DFS)’는 특정 질환(예를 들어 암)에 대한 치료 후 질환이 재발한 환자가 생존하는 기간을 포함한다. In the present invention, the term 'disease-free survival (DFS)' includes a period in which a patient who relapses after a treatment for a specific disease (eg, cancer) survives.
본 발명은 전립선암 환자의 샘플에서 본 발명의 유전자의 돌연변이의 존재를 분석함으로써 대상 시료를 가진 개체가 암에 대해 어떤 예후를 가지는지를 확인할 수 있다. 또한 이러한 방법은 예후가 좋다고 알려진 돌연변이가 존재하지 않는 대조군의 개체의 총 생존율 또는 무병 생존율을 비교함으로써 달성될 수 있다. 본 발명에서 예후가 좋다고 알려진 개체란 암이 발병한 후에 전이, 재발, 사망 등의 이력이 없는 개체를 의미한다.The present invention can confirm the prognosis for cancer of an individual with a target sample by analyzing the presence of a mutation of the gene of the present invention in a sample of a patient with prostate cancer. In addition, this method can be achieved by comparing the total survival rate or disease-free survival rate of an individual in a control group free of mutations known to have a good prognosis. In the present invention, an individual known to have a good prognosis means an individual who has no history of metastasis, recurrence, death, etc. after cancer has developed.
암이 의심되는 개체의 샘플이란 암 또는 종양이 이미 발생하였거나 발생할 것으로 예상되는 개체 또는 조직의 시료로써, 그 예후를 진단하고자 하는 대상 시료를 의미한다.A sample of an individual suspected of cancer is a sample of an individual or tissue in which cancer or a tumor has already occurred or is expected to occur, and refers to a sample for which the prognosis is to be diagnosed.
상기 CPXM1, 및 MYH11로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자에서 돌연변이가 확인되는 경우, 상기 대상체의 생존율이 양호하지 않은 것으로 판단하는 단계;를 더 포함할 수 있다.If the mutation is identified in at least one gene selected from the gene group consisting of CPXM1 and MYH11, determining that the survival rate of the subject is not good may further include.
본 발명의 한 실시예에 있어서, CPXM1, 및 MYH11로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자에서 돌연변이가 발생한 전립선암 환자의 경우 해당 유전자에 돌연변이가 발생하지 않은 전립선암 환자에 비해서 생존율이 낮았다(표 1 참조). In one embodiment of the present invention, in the case of a prostate cancer patient mutated from at least one gene selected from the gene group consisting of CPXM1 and MYH11, the survival rate was lower than that of a prostate cancer patient in which the gene was not mutated ( See Table 1).
실시예에 있어서, AGXT2, ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, 및 SERINC3로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자에서 돌연변이가 발생한 전립선암 환자의 경우 해당 유전자에 돌연변이가 발생하지 않은 전립선암 환자에 비해서 재발율이 높았다(표 1 참조).In an embodiment, a prostate cancer patient mutated from at least one gene selected from the gene group consisting of AGXT2, ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, and SERINC3 In this case, the recurrence rate was higher than that of patients with prostate cancer who did not have a mutation in the gene (see Table 1).
상기 AGXT2, ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, 및 SERINC3로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자에서 돌연변이가 확인되는 경우, 상기 대상체의 전립선암의 재발율이 높은 것으로 판단하는 단계;를 더 포함할 수 있다. Prostate cancer of the subject when mutations are identified in at least one gene selected from the gene group consisting of AGXT2, ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, and SERINC3 Determining that the recurrence rate of is high; may further include.
본 발명의 한 실시예에 있어서, AGXT2, ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, 및 SERINC3로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자에서 돌연변이가 발생한 전립선암 환자의 경우 해당 유전자에 돌연변이가 발생하지 않은 전립선암 환자에 비해서 전립선암의 재발율이 높았다(표 1 참조).In one embodiment of the present invention, mutations are generated in at least one gene selected from the gene group consisting of AGXT2, ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, and SERINC3. In patients with prostate cancer, the recurrence rate of prostate cancer was higher than that of patients with prostate cancer who did not have a mutation in the gene (see Table 1).
이와 같이, 본 발명의 유전자의 돌연변이인 AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8 로 구성된 유전자 군에서 선택되는 적어도 하나의 유전자의 돌연변이를 이용하여 암, 특히 전립선암에 대한 예후를 진단가능하다는 내용에 대해서는 아직까지 밝혀진 바 없다. 또한, 각 유전자에서 총 생존율 또는 무병 생존율이 상이할 수 있는 점에 대해서도 보고된 바 없다. 본 발명자는 상기 유전자들의 변이체를 전립선암 환자의 예후를 진단할 수 있는 진단 표지자로 사용할 수 있는 점을 최초로 규명하였다. As such, at least one gene selected from the gene group consisting of mutations of the genes of the present invention AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8 The prognosis for cancer, in particular prostate cancer, can be diagnosed using the mutation of, has not been revealed. In addition, it has not been reported that the total survival rate or disease-free survival rate in each gene may be different. The present inventors first identified the point that the variants of the genes can be used as diagnostic markers to diagnose the prognosis of a patient with prostate cancer.
본 발명의 전립선암의 재발 예후 진단을 위해 필요한 정보를 제공하는 방법은 전립선암 환자의 생존율을 높이거나, 또는, 재발률을 낮추는데 사용될 수 있다. 본 발명의 전립선암의 예후 진단에 대한 방법을 통해, 전립선암 환자의 생존율 또는, 재발률을 예측할 수 있으므로, 각 환자에 적합한 치료제 발굴뿐만 아니라, 치료법 선택에 있어 정보를 제공할 수 있어, 전립선암에 관한 치료적 전략을 효율적으로 설계할 수 있다. 이하, 본 발명을 실시예 및 실험예에 의해 상세히 설명한다. 단, 하기 실시예 및 실험예는 본 발명을 예시하기 위한 것일 뿐, 본 발명의 내용이 하기 실시예 및 실험예에 의해 한정되는 것은 아니다. The method of providing information necessary for the diagnosis of prognosis of recurrence of prostate cancer of the present invention may be used to increase the survival rate of prostate cancer patients or to reduce the recurrence rate. Through the method for prognostic diagnosis of prostate cancer of the present invention, the survival rate or recurrence rate of a patient with prostate cancer can be predicted, and thus, not only the discovery of a therapeutic agent suitable for each patient, but also information in selecting a treatment method can be provided. Therapeutic strategies can be efficiently designed. Hereinafter, the present invention will be described in detail by examples and experimental examples. However, the following examples and experimental examples are only for illustrating the present invention, and the contents of the present invention are not limited by the following examples and experimental examples.
유전 정보 및 임상 정보의 확보Secure genetic and clinical information
먼저, 본 발명의 유전자들(AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3, SLC38A8)을 전립선암 마커로서 활용할 수 있는지 여부를 확인하기 위하여, TCGA(The Cancer Genome Atlas)로부터 유전 정보와 임상 정보가 모두 확보되어 있는 전립선암 환자 484명의 데이터를 입수하여 분석에 이용하였다. First, confirm whether the genes of the present invention (AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3, SLC38A8) can be used as prostate cancer markers To this end, data from 484 patients with prostate cancer, both genetic and clinical information, were obtained from The Cancer Genome Atlas (TCGA) and used for analysis.
하기 표 1 의 각 유전자의 돌연변이 개수, 돌연변이율, 돌연변이 유형, 사이토밴드, 생존 사망에 대한 Fisher의 정확한 검정. 또한, 각 유전자의 돌연변이된 위치를 표 1 에 나타낸다. 총 생존 기간(overall survival kaplan-meier estimate) 및 무병 생존 기간(disease free survival kaplan-meier estimate)은 하기 실시예 2와 같이 카플란 마이어 생존 분석법(Spss 21, cbioportal)으로 구하였다. 총 생존 기간에서는 사건을 사망으로 정하고, 무병 생존 기간에서는 사건을 전립선암의 재발로 정하였다. 상기 유전자들 각각에서의 돌연변이 발생이 전립선암에 의한 사망 또는, 전립선암의 재발과 상호 관련성이 있는지 여부를 확인하기 위하여, 카플란 마이어 생존 분석법에서 얻어진 각 군의 사건 시간(event time)을 토대로 돌연변이 발생과 총 생존 기간의 연관성, 및 돌연변이 발생과 무병 생존 기간의 연관성을 로그순위 검정(log rank test)에 의해 확인하였다. 0.05 미만의 P-value를 통계적으로 유의한 것으로 간주하였다. Fisher's exact assay for the number of mutations, mutation rate, mutation type, cytoband, and survival death of each gene in Table 1 below. In addition, Table 1 shows the mutated positions of each gene. The total survival kaplan-meier estimate and disease free survival kaplan-meier estimate were determined by Kaplan Meyer survival analysis (Spss 21, cbioportal) as in Example 2 below. In total survival, the event was defined as death, and in disease-free survival, the event was defined as recurrence of prostate cancer. To determine whether mutations in each of the genes are correlated with death from prostate cancer or recurrence of prostate cancer, mutations are generated based on the event time of each group obtained from Kaplan Meyer Survival Assay. And the relationship between the total survival time and the association between mutation occurrence and disease-free survival time were confirmed by a log rank test. P-values less than 0.05 were considered statistically significant.
확인한 결과, 본 발명의 유전자(AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8)에 돌연변이가 발생한 경우, P-value가 0.05 미만으로 총 생존율 또는 무병 생존율과 연관성이 있는 것으로 확인되었다. As a result, if the genes of the present invention (AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8) have a mutation, the P-value is less than 0.05 As a result, it was confirmed to be related to the overall survival rate or the disease-free survival rate.
이와 같이, 전립선암 환자에서 특이적으로 돌연변이가 발생한 유전자라고 하더라도, 유전자에 따라서 해당 유전자의 돌연변이와 총 생존 기간의 상관관계, 또는 해당 유전자의 돌연변이와 무병 생존 기간의 상관관계가 다른 것을 알 수 있었다. 실시예 2에는 돌연변이와 총 생존/무병 생존 기간이 매우 유의한 상관관계가 있었던 본 발명의 유전자들의 생존 분석 결과를 나타낸다. As described above, even if the gene was specifically mutated in patients with prostate cancer, it was found that the correlation between the mutation of the gene and the total survival period, or the correlation between the mutation of the gene and the disease-free survival period, depends on the gene. . Example 2 shows the results of the survival analysis of the genes of the present invention, in which the mutation and the total survival / no disease survival period were significantly correlated.
재발 특이적 마커로서의 활용 가능성 확인 Confirmation of potential use as a recurrence specific marker
상기 실시예 1에서 확보된 484명의 대상 환자를 비재발 환자(395명)과 재발 환자(89명)으로 분류하고, 비교 분석을 실시하였다. 전체 전립선암 환자 484명 중에서 재발 환자는 89명으로 18%를 차지하였다. 실시예 1에서 확보한 임상 정보(사건(사망 또는 재발) 여부, 관측 시간)을 토대로 카플란 마이어 생존 분석법으로 총 생존 기간 또는 무병 생존 기간을 계산하였다. 실험군은 본 발명의 유전자들에 돌연변이가 있는 경우(case with alterations in query gene)로 하였고, 대조군으로는 본 발명의 유전자들에 돌연변이가 없는 경우(case without alterations in query gene)로 하였다. 각 유전자에 대한 생존 분석 결과를 도 1 내지 도 16에 나타낸다. 생존 기간 중앙값(median months survival)은 해당 군의 환자들의 생존 기간을 나열하였을 때 중앙에 위치하는 값을 의미한다. 카플란 마이어 생존 분석법에 의한 생존 곡선에서의 경사도는 생존 기간에 의해 결정된다.The 484 subjects obtained in Example 1 were classified into non-relapse patients (395 patients) and relapse patients (89 patients), and comparative analysis was performed. Of the 484 patients with prostate cancer, 89 patients had relapses, accounting for 18%. Based on the clinical information (event (death or relapse), observation time) obtained in Example 1, the total survival or disease-free survival was calculated by Kaplan Meyer survival analysis. The experimental group was set as the case of mutations in the genes of the present invention (case with alterations in query gene), and the control group was set as the case of no mutations in the genes of the present invention (case without alterations in query gene). Results of survival analysis for each gene are shown in FIGS. 1 to 16. The median months survival means the median value when the patients' survival periods are listed. The slope in the survival curve by Kaplan Meyer survival method is determined by the duration of survival.
그 결과, 본 발명의 유전자들에 돌연변이가 있는 경우에 생존 기간 중앙값의 평균이 약 71개월이고, 본 발명의 유전자들에 돌연변이가 없는 경우에 생존 기간 중앙값의 평균은 약 115개월로서, 본 발명의 유전자들에 돌연변이가 있는 경우에 생존 기간 중앙값이 낮은 편인 것을 알 수 있었다. As a result, when the genes of the present invention are mutated, the median survival time is about 71 months, and when the genes of the present invention are not mutated, the median survival time is about 115 months. It was found that the median survival time was low when the genes were mutated.
본 발명의 유전자들에 돌연변이가 있는 경우에 재발 측정 기간 중앙값의 평균이 약 23개월이고, 본 발명의 유전자들에 돌연변이가 없는 경우에 재발 측정 기간 중앙값의 평균은 약 85개월로서, 본 발명의 유전자들에 돌연변이가 있는 경우에 재발 발병 가능성의 중앙값이 훨씬 낮은 것을 알 수 있었다When the genes of the present invention have a mutation, the median of the recurrence measurement period median is about 23 months, and when there are no mutations in the genes of the present invention, the median of the recurrence measurement period median is about 85 months. It was found that the median probability of recurrence was much lower when there was a mutation in the field
AGXT2 는 도 2의 (B)에서 알 수 있는 바 같이, 상기 AGXT2 유전자에 돌연변이가 발생하지 않은 전립선암 환자의 경우 18% 이상이 약 80개월 이상 무병으로 비재발한 것에 반해(청색), 상기 AGXT2 유전자에 돌연변이가 발생한 전립선암 환자는 전립선암 환자의 100% 이상이 돌연변이가 발생하지 않은 전립선암 환자보다 약 3개월 기간내로 재발하였으므로 돌연변이가 발생하지 않은 전립선암 환자에 비해서 재발률이 높은 것으로 확인되었다(적색). 따라서, AGXT2 유전자에 돌연변이가 있을 때에 전립선암에 의한 재발 확률이 높아지므로 상기 유전자의 돌연변이가 전립선암 환자의 재발 예측 마커로서 유의함을 알 수 있다.As can be seen from FIG. 2 (B), AGXT2 is 18% or more of patients with prostate cancer who have not been mutated to the AGXT2 gene, but has not recurred disease-free for more than about 80 months (blue), the AGXT2 Prostate cancer patients with mutations in the gene were found to have a higher recurrence rate compared to those with no mutations, as 100% or more of the patients with prostate cancer relapsed within about 3 months than those with no mutations. Red). Therefore, it can be seen that when the AGXT2 gene is mutated, the probability of recurrence due to prostate cancer increases, and thus the mutation of the gene is significant as a predictor of recurrence in patients with prostate cancer.
ATG2A는 도 3의 (B)에서 알 수 있는 바 같이, 상기 ATG2A 유전자에 돌연변이가 발생하지 않은 전립선암 환자의 경우 18% 이상이 약 90개월 이상 무병으로 비재발한 것에 반해(청색), 상기 ATG2A 유전자에 돌연변이가 발생한 전립선암 환자는 전립선암 환자의 100% 이상이 돌연변이가 발생하지 않은 전립선암 환자보다 약 23개월 기간내로 재발하였으므로 돌연변이가 발생하지 않은 전립선암 환자에 비해서 재발률이 높은 것으로 확인되었다(적색). 따라서, ATG2A 유전자에 돌연변이가 있을 때에 전립선암에 의한 재발 확률이 높아지므로 상기 유전자의 돌연변이가 전립선암 환자의 재발 예측 마커로서 유의함을 알 수 있다. 상기 AGXT2 및 ATG2A 처럼 ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3는 도 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 내지 도 16에서 알 수 있는 바와 같이, 총 무병 생존율에서 돌연변이가 발생한 환자에서 유의하게 짧았다. 따라서, 상기 ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC 유전자의 돌연변이가 전립선암의 재발 예측 마커로서 유의함을 알 수 있다.ATG2A, as can be seen in FIG. 3 (B), 18% or more of patients with prostate cancer who have not been mutated to the ATG2A gene have non-relapse without disease for at least 90 months (blue), the ATG2A Prostate cancer patients with mutations in the gene were found to have a higher recurrence rate than prostate cancer patients without mutations, because more than 100% of the patients with prostate cancer relapsed within about 23 months compared to those with no mutations. Red). Therefore, it can be seen that when the ATG2A gene is mutated, the probability of recurrence due to prostate cancer is increased, and thus the mutation of the gene is significant as a predictor of recurrence in patients with prostate cancer. Like AGXT2 and ATG2A, ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 are shown in Figures 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, As can be seen from 15 to 16, the total disease-free survival rate was significantly shorter in the mutated patient. Therefore, it can be seen that the mutations of the ATP13A5, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, and SERINC genes are significant as predictors of recurrence of prostate cancer.
CPXM1 및 MYH11 유전자는 도 7 및 도 12의 (A)에서 알 수 있는 바 같이, 상기 CPXM1 및 MYH11 유전자에 돌연변이가 발생하지 않은 전립선암 환자의 경우 0.62% 이상이 약 120개월 이상 생존한데 반해(청색), 상기 CPXM1 및 MYH11 유전자에 돌연변이가 발생한 전립선암 환자는 전립선암 환자의 약 16~50% 이상이 돌연변이가 발생하지 않은 전립선암 환자보다 적은 개월 수를 생존하고, 사망하였으므로 돌연변이가 발생하지 않은 전립선암 환자에 비해서 생존율이 낮은 것으로 확인되었다(적색). 따라서, 전립선암 환자의 생존율 또는 전립선암의 재발 예측 마커로서 유의함을 알 수 있다. 위 결과를 통해서, 전립선암 환자 중 본 발명의 유전자들에 돌연변이가 있는 경우 생존율이 현저히 낮아지거나, 재발율이 증가하는 것을 알 수 있으므로, 본 발명의 유전자들에 돌연변이가 있는지 여부를 통해 전립선암의 예후, 특히 생존 여부 또는 재발 여부를 예측할 수 있음을 알 수 있다.CPXM1 and MYH11 genes, as can be seen in Figures 7 and 12 (A), the CPXM1 and MYH11 genes in the case of prostate cancer patients without mutations, 0.62% or more survived for about 120 months or more (blue ), About 16-50% of patients with prostate cancer mutated with CPXM1 and MYH11 genes survived fewer months than patients with prostate cancer without mutation, and died because prostate cancer did not occur. It was confirmed that the survival rate was lower than that of cancer patients (red). Therefore, it can be seen that the survival rate of patients with prostate cancer is significant as a predictor of recurrence of prostate cancer. Through the above results, it can be seen that the survival rate is significantly lowered or the recurrence rate increases when the genes of the present invention are mutated among patients with prostate cancer, and thus the prognosis of prostate cancer is determined by whether the genes of the present invention have mutations. In particular, it can be seen that the survival or recurrence can be predicted.
실시예 2의 유전자의 돌연변이를 검출가능한 칩의 제작Preparation of a chip capable of detecting the mutation of the gene of Example 2
실시예 2의 유전자의 돌연변이 검색을 위한 프라이머 세트는 https://tools.thermofisher.com/content/sfs/manuals/MAN0006735_AmpliSeq_DNA_RNA_LibPrep_UG.pdf를 참고하여 Thermo fisher의 Ion AmpliSeq? Custom and Community Panels로 제작하였다. 돌연변이를 용이하게 검출하기 위해서, chip 종류를 선택하고 Depth를 높였다. 구체적으로 Ampliseq.com에 제작하고자 하는 패널 정보를 입력하고, 입력된 정보에 대해서 피드백을 받은 후, 관련 사항에 대해서 논의하여 돌연변이를 검출할 수 있는 프라이머 세트가 탑재된 패널을 제작하였다. 표 2에 본 발명의 유전자의 돌연변이를 검출할 수 있는 프라이머 세트를 나타낸다. For a primer set for mutant search of the gene of Example 2, refer to https://tools.thermofisher.com/content/sfs/manuals/MAN0006735_AmpliSeq_DNA_RNA_LibPrep_UG.pdf Ion AmpliSeq? Made with Custom and Community Panels. In order to detect the mutation easily, the chip type was selected and the depth was increased. Specifically, after inputting the panel information to be produced on Ampliseq.com, receiving feedback on the inputted information, and discussing the related matters, a panel equipped with a primer set capable of detecting mutations was produced. Table 2 shows a primer set capable of detecting a mutation in the gene of the present invention.
제작된 프라이머 세트로 돌연변이 검출이 가능한지 소프트웨어를 이용하여 분석하였다. 그 결과, 실시예 3에서 제작한 프라이머 세트로 실시예 2의 유전자의 돌연변이를 검출 가능하다는 것이 나타났다. 반면에, 대조군인 전립선암 세포에서 유래한 시료에서는 돌연변이가 검출되지 않았다. 이와 같이 표 2의 프라이머 쌍을 이용하여 AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 및 SLC38A8로 구성된 유전자 군에서 선택되는 유전자의 변이를 각각 검출가능 하므로, 상기 유전자들의 변이가 나타난 전립선암 환자의 총 생존 기간, 무병 생존 기간을 예측할 수 있고, 이에 따라 치료 전략을 효율적으로 설계할 수 있다. 상기에서는 본 발명의 바람직한 실시예를 예시적으로 설명하였으나, 본 발명의 범위는 상기와 같은 특정 실시예에만 한정되지 아니하며, 해당 분야에서 통상의 지식을 가진 자라면 본 발명의 특허청구범위에 기재된 범주 내에서 적절하게 변경이 가능할 것이다.It was analyzed by using the software whether mutation detection is possible with the prepared primer set. As a result, it was found that the mutation of the gene of Example 2 can be detected with the primer set prepared in Example 3. On the other hand, no mutation was detected in the sample derived from the control prostate cancer cells. As described above, using the primer pair of Table 2, mutations of genes selected from the gene group consisting of AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC3 and SLC38A8 are used. Since each is detectable, it is possible to predict the total survival time and disease-free survival time of patients with prostate cancer in which mutations of the genes appear, and accordingly, a treatment strategy can be efficiently designed. In the above, the preferred embodiment of the present invention has been exemplarily described, but the scope of the present invention is not limited only to the specific embodiment as described above, and a person having ordinary knowledge in the field, the category described in the claims of the present invention Changes can be made as appropriate within.
<110> CHO, Han-Jun <120> Gene mutations biomarker that predicts recurrence for prostate cancer <130> P-20200303 <160> 30 <170> KoPatentIn 3.0 <210> 1 <211> 514 <212> PRT <213> Homo sapiens <400> 1 Met Thr Leu Ile Trp Arg His Leu Leu Arg Pro Leu Cys Leu Val Thr 1 5 10 15 Ser Ala Pro Arg Ile Leu Glu Met His Pro Phe Leu Ser Leu Gly Thr 20 25 30 Ser Arg Thr Ser Val Thr Lys Leu Ser Leu His Thr Lys Pro Arg Met 35 40 45 Pro Pro Cys Asp Phe Met Pro Glu Arg Tyr Gln Ser Leu Gly Tyr Asn 50 55 60 Arg Val Leu Glu Ile His Lys Glu His Leu Ser Pro Val Val Thr Ala 65 70 75 80 Tyr Phe Gln Lys Pro Leu Leu Leu His Gln Gly His Met Glu Trp Leu 85 90 95 Phe Asp Ala Glu Gly Ser Arg Tyr Leu Asp Phe Phe Ser Gly Ile Val 100 105 110 Thr Val Ser Val Gly His Cys His Pro Lys Val Asn Ala Val Ala Gln 115 120 125 Lys Gln Leu Gly Arg Leu Trp His Thr Ser Thr Val Phe Phe His Pro 130 135 140 Pro Met His Glu Tyr Ala Glu Lys Leu Ala Ala Leu Leu Pro Glu Pro 145 150 155 160 Leu Lys Val Ile Phe Leu Val Asn Ser Gly Ser Glu Ala Asn Glu Leu 165 170 175 Ala Met Leu Met Ala Arg Ala His Ser Asn Asn Ile Asp Ile Ile Ser 180 185 190 Phe Arg Gly Ala Tyr His Gly Cys Ser Pro Tyr Thr Leu Gly Leu Thr 195 200 205 Asn Val Gly Thr Tyr Lys Met Glu Leu Pro Gly Gly Thr Gly Cys Gln 210 215 220 Pro Thr Met Cys Pro Asp Val Phe Arg Gly Pro Trp Gly Gly Ser His 225 230 235 240 Cys Arg Asp Ser Pro Val Gln Thr Ile Arg Lys Cys Ser Cys Ala Pro 245 250 255 Asp Cys Cys Gln Ala Lys Asp Gln Tyr Ile Glu Gln Phe Lys Asp Thr 260 265 270 Leu Ser Thr Ser Val Ala Lys Ser Ile Ala Gly Phe Phe Ala Glu Pro 275 280 285 Ile Gln Gly Val Asn Gly Val Val Gln Tyr Pro Lys Gly Phe Leu Lys 290 295 300 Glu Ala Phe Glu Leu Val Arg Ala Arg Gly Gly Val Cys Ile Ala Asp 305 310 315 320 Glu Val Gln Thr Gly Phe Gly Arg Leu Gly Ser His Phe Trp Gly Phe 325 330 335 Gln Thr His Asp Val Leu Pro Asp Ile Val Thr Met Ala Lys Gly Ile 340 345 350 Gly Asn Gly Phe Pro Met Ala Ala Val Ile Thr Thr Pro Glu Ile Ala 355 360 365 Lys Ser Leu Ala Lys Cys Leu Gln His Phe Asn Thr Phe Gly Gly Asn 370 375 380 Pro Met Ala Cys Ala Ile Gly Ser Ala Val Leu Glu Val Ile Lys Glu 385 390 395 400 Glu Asn Leu Gln Glu Asn Ser Gln Glu Val Gly Thr Tyr Met Leu Leu 405 410 415 Lys Phe Ala Lys Leu Arg Asp Glu Phe Glu Ile Val Gly Asp Val Arg 420 425 430 Gly Lys Gly Leu Met Ile Gly Ile Glu Met Val Gln Asp Lys Ile Ser 435 440 445 Cys Arg Pro Leu Pro Arg Glu Glu Val Asn Gln Ile His Glu Asp Cys 450 455 460 Lys His Met Gly Leu Leu Val Gly Arg Gly Ser Ile Phe Ser Gln Thr 465 470 475 480 Phe Arg Ile Ala Pro Ser Met Cys Ile Thr Lys Pro Glu Val Asp Phe 485 490 495 Ala Val Glu Val Phe Arg Ser Ala Leu Thr Gln His Met Glu Arg Arg 500 505 510 Ala Lys <210> 2 <211> 1938 <212> PRT <213> Homo sapiens <400> 2 Met Ser Arg Trp Leu Trp Pro Trp Ser Asn Cys Val Lys Glu Arg Val 1 5 10 15 Cys Arg Tyr Leu Leu His His Tyr Leu Gly His Phe Phe Gln Glu His 20 25 30 Leu Ser Leu Asp Gln Leu Ser Leu Asp Leu Tyr Lys Gly Ser Val Ala 35 40 45 Leu Arg Asp Ile His Leu Glu Ile Trp Ser Val Asn Glu Val Leu Glu 50 55 60 Ser Met Glu Ser Pro Leu Glu Leu Val Glu Gly Phe Val Gly Ser Ile 65 70 75 80 Glu Val Ala Val Pro Trp Ala Ala Leu Leu Thr Asp His Cys Thr Val 85 90 95 Arg Val Ser Gly Leu Gln Leu Thr Leu Gln Pro Arg Arg Gly Pro Ala 100 105 110 Pro Gly Ala Ala Asp Ser Gln Ser Trp Ala Ser Cys Met Thr Thr Ser 115 120 125 Leu Gln Leu Ala Gln Glu Cys Leu Arg Asp Gly Leu Pro Glu Pro Ser 130 135 140 Glu Pro Pro Gln Pro Leu Glu Gly Leu Glu Met Phe Ala Gln Thr Ile 145 150 155 160 Glu Thr Val Leu Arg Arg Ile Lys Val Thr Phe Leu Asp Thr Val Val 165 170 175 Arg Val Glu His Ser Pro Gly Asp Gly Glu Arg Gly Val Ala Val Glu 180 185 190 Val Arg Val Gln Arg Leu Glu Tyr Cys Asp Glu Ala Val Arg Asp Pro 195 200 205 Ser Gln Ala Pro Pro Val Asp Val His Gln Pro Pro Ala Phe Leu His 210 215 220 Lys Leu Leu Gln Leu Ala Gly Val Arg Leu His Tyr Glu Glu Leu Pro 225 230 235 240 Ala Gln Glu Glu Pro Pro Glu Pro Pro Leu Gln Ile Gly Ser Cys Ser 245 250 255 Gly Tyr Met Glu Leu Met Val Lys Leu Lys Gln Asn Glu Ala Phe Pro 260 265 270 Gly Pro Lys Leu Glu Val Ala Gly Gln Leu Gly Ser Leu His Leu Leu 275 280 285 Leu Thr Pro Arg Gln Leu Gln Gln Leu Gln Glu Leu Leu Ser Ala Val 290 295 300 Ser Leu Thr Asp His Glu Gly Leu Ala Asp Lys Leu Asn Lys Ser Arg 305 310 315 320 Pro Leu Gly Ala Glu Asp Leu Trp Leu Ile Glu Gln Asp Leu Asn Gln 325 330 335 Gln Leu Gln Ala Gly Ala Val Ala Glu Pro Leu Ser Pro Asp Pro Leu 340 345 350 Thr Asn Pro Leu Leu Asn Leu Asp Asn Thr Asp Leu Phe Phe Ser Met 355 360 365 Ala Gly Leu Thr Ser Ser Val Ala Ser Ala Leu Ser Glu Leu Ser Leu 370 375 380 Ser Asp Val Asp Leu Ala Ser Ser Val Arg Ser Asp Met Ala Ser Arg 385 390 395 400 Arg Leu Ser Ala Gln Ala His Pro Ala Gly Lys Met Ala Pro Asn Pro 405 410 415 Leu Leu Asp Thr Met Arg Pro Asp Ser Leu Leu Lys Met Thr Leu Gly 420 425 430 Gly Val Thr Leu Thr Leu Leu Gln Thr Ser Ala Pro Ser Ser Gly Pro 435 440 445 Pro Asp Leu Ala Thr His Phe Phe Thr Glu Phe Asp Ala Thr Lys Asp 450 455 460 Gly Pro Phe Gly Ser Arg Asp Phe His His Leu Arg Pro Arg Phe Gln 465 470 475 480 Arg Ala Cys Pro Cys Ser His Val Arg Leu Thr Gly Thr Ala Val Gln 485 490 495 Leu Ser Trp Glu Leu Arg Thr Gly Ser Arg Gly Arg Arg Thr Thr Ser 500 505 510 Met Glu Val His Phe Gly Gln Leu Glu Val Leu Glu Cys Leu Trp Pro 515 520 525 Arg Gly Thr Ser Glu Pro Glu Tyr Thr Glu Ile Leu Thr Phe Pro Gly 530 535 540 Thr Leu Gly Ser Gln Ala Ser Ala Arg Pro Cys Ala His Leu Arg His 545 550 555 560 Thr Gln Ile Leu Arg Arg Val Pro Lys Ser Arg Pro Arg Arg Ser Val 565 570 575 Ala Cys His Cys His Ser Glu Leu Ala Leu Asp Leu Ala Asn Phe Gln 580 585 590 Ala Asp Val Glu Leu Gly Ala Leu Asp Arg Leu Ala Ala Leu Leu Arg 595 600 605 Leu Ala Thr Val Pro Ala Glu Pro Pro Ala Gly Leu Leu Thr Glu Pro 610 615 620 Leu Pro Ala Met Glu Gln Gln Thr Val Phe Arg Leu Ser Ala Pro Arg 625 630 635 640 Ala Thr Leu Arg Leu Arg Phe Pro Ile Ala Asp Leu Arg Pro Glu Pro 645 650 655 Asp Pro Trp Ala Gly Gln Ala Val Arg Ala Glu Gln Leu Arg Leu Glu 660 665 670 Leu Ser Glu Pro Gln Phe Arg Ser Glu Leu Ser Ser Gly Pro Gly Pro 675 680 685 Pro Val Pro Thr His Leu Glu Leu Thr Cys Ser Asp Leu His Gly Ile 690 695 700 Tyr Glu Asp Gly Gly Lys Pro Pro Val Pro Cys Leu Arg Val Ser Lys 705 710 715 720 Ala Leu Asp Pro Lys Ser Thr Gly Arg Lys Tyr Phe Leu Pro Gln Val 725 730 735 Val Val Thr Val Asn Pro Gln Ser Ser Ser Thr Gln Trp Glu Val Ala 740 745 750 Pro Glu Lys Gly Glu Glu Leu Glu Leu Ser Val Glu Ser Pro Cys Glu 755 760 765 Leu Arg Glu Pro Glu Pro Ser Pro Phe Ser Ser Lys Arg Thr Met Tyr 770 775 780 Glu Thr Glu Glu Met Val Ile Pro Gly Asp Pro Glu Glu Met Arg Thr 785 790 795 800 Phe Gln Ser Arg Thr Leu Ala Leu Ser Arg Cys Ser Leu Glu Val Ile 805 810 815 Leu Pro Ser Val His Ile Phe Leu Pro Ser Lys Glu Val Tyr Glu Ser 820 825 830 Ile Tyr Asn Arg Ile Asn Asn Asp Leu Leu Met Trp Glu Pro Ala Asp 835 840 845 Leu Leu Pro Thr Pro Asp Pro Ala Ala Gln Pro Ser Gly Phe Pro Gly 850 855 860 Pro Ser Gly Phe Trp His Asp Ser Phe Lys Met Cys Lys Ser Ala Phe 865 870 875 880 Lys Leu Ala Asn Cys Phe Asp Leu Thr Pro Asp Ser Asp Ser Asp Asp 885 890 895 Glu Asp Ala His Phe Phe Ser Val Gly Ala Ser Gly Gly Pro Gln Ala 900 905 910 Ala Ala Pro Glu Ala Pro Ser Leu His Leu Gln Ser Thr Phe Ser Thr 915 920 925 Leu Val Thr Val Leu Lys Gly Arg Ile Thr Ala Leu Cys Glu Thr Lys 930 935 940 Asp Glu Gly Gly Lys Arg Leu Glu Ala Val His Gly Glu Leu Val Leu 945 950 955 960 Asp Met Glu His Gly Thr Leu Phe Ser Val Ser Gln Tyr Cys Gly Gln 965 970 975 Pro Gly Leu Gly Tyr Phe Cys Leu Glu Ala Glu Lys Ala Thr Leu Tyr 980 985 990 His Arg Ala Ala Val Asp Asp Tyr Pro Leu Pro Ser His Leu Asp Leu 995 1000 1005 Pro Ser Phe Ala Pro Pro Ala Gln Leu Ala Pro Thr Ile Tyr Pro Ser 1010 1015 1020 Glu Glu Gly Val Thr Glu Arg Gly Ala Ser Gly Arg Lys Gly Gln Gly 1025 1030 1035 1040 Arg Gly Pro His Met Leu Ser Thr Ala Val Arg Ile His Leu Asp Pro 1045 1050 1055 His Lys Asn Val Lys Glu Phe Leu Val Thr Leu Arg Leu His Lys Ala 1060 1065 1070 Thr Leu Arg His Tyr Met Ala Leu Pro Glu Gln Ser Trp His Ser Gln 1075 1080 1085 Leu Leu Glu Phe Leu Asp Val Leu Asp Asp Pro Val Leu Gly Tyr Leu 1090 1095 1100 Pro Pro Thr Val Ile Thr Ile Leu His Thr His Leu Phe Ser Cys Ser 1105 1110 1115 1120 Val Asp Tyr Arg Pro Leu Tyr Leu Pro Val Arg Val Leu Ile Thr Ala 1125 1130 1135 Glu Thr Phe Thr Leu Ser Ser Asn Ile Ile Met Asp Thr Ser Thr Phe 1140 1145 1150 Leu Leu Arg Phe Ile Leu Asp Asp Ser Ala Leu Tyr Leu Ser Asp Lys 1155 1160 1165 Cys Glu Val Glu Thr Leu Asp Leu Arg Arg Asp Tyr Val Cys Val Leu 1170 1175 1180 Asp Val Asp Leu Leu Glu Leu Val Ile Lys Thr Trp Lys Gly Ser Thr 1185 1190 1195 1200 Glu Gly Lys Leu Ser Gln Pro Leu Phe Glu Leu Arg Cys Ser Asn Asn 1205 1210 1215 Val Val His Val His Ser Cys Ala Asp Ser Cys Ala Leu Leu Val Asn 1220 1225 1230 Leu Leu Gln Tyr Val Met Ser Thr Gly Asp Leu His Pro Pro Pro Arg 1235 1240 1245 Pro Pro Ser Pro Thr Glu Ile Ala Gly Gln Lys Leu Ser Glu Ser Pro 1250 1255 1260 Ala Ser Leu Pro Ser Cys Pro Pro Val Glu Thr Ala Leu Ile Asn Gln 1265 1270 1275 1280 Arg Asp Leu Ala Asp Ala Leu Leu Asp Thr Glu Arg Ser Leu Arg Glu 1285 1290 1295 Leu Ala Gln Pro Ser Gly Gly His Leu Pro Gln Ala Ser Pro Ile Ser 1300 1305 1310 Val Tyr Leu Phe Pro Gly Glu Arg Ser Gly Ala Pro Pro Pro Ser Pro 1315 1320 1325 Pro Val Gly Gly Pro Ala Gly Ser Leu Gly Ser Cys Ser Glu Glu Lys 1330 1335 1340 Glu Asp Glu Arg Glu Glu Glu Gly Asp Gly Asp Thr Leu Asp Ser Asp 1345 1350 1355 1360 Glu Phe Cys Ile Leu Asp Ala Pro Gly Leu Gly Ile Pro Pro Arg Asp 1365 1370 1375 Gly Glu Pro Val Val Thr Gln Leu His Pro Gly Pro Ile Val Val Arg 1380 1385 1390 Asp Gly Tyr Phe Ser Arg Pro Ile Gly Ser Thr Asp Leu Leu Arg Ala 1395 1400 1405 Pro Ala His Phe Pro Val Pro Ser Thr Arg Val Val Leu Arg Glu Val 1410 1415 1420 Ser Leu Val Trp His Leu Tyr Gly Gly Arg Asp Phe Gly Pro His Pro 1425 1430 1435 1440 Gly His Arg Ala Arg Thr Gly Leu Ser Gly Pro Arg Ser Ser Pro Ser 1445 1450 1455 Arg Cys Ser Gly Pro Asn Arg Pro Gln Asn Ser Trp Arg Thr Gln Gly 1460 1465 1470 Gly Ser Gly Arg Gln His His Val Leu Met Glu Ile Gln Leu Ser Lys 1475 1480 1485 Val Ser Phe Gln His Glu Val Tyr Pro Ala Glu Pro Ala Thr Gly Pro 1490 1495 1500 Ala Ala Pro Ser Gln Glu Leu Glu Glu Arg Pro Leu Ser Arg Gln Val 1505 1510 1515 1520 Phe Ile Val Gln Glu Leu Glu Val Arg Asp Arg Leu Ala Ser Ser Gln 1525 1530 1535 Ile Asn Lys Phe Leu Tyr Leu His Thr Ser Glu Arg Met Pro Arg Arg 1540 1545 1550 Ala His Ser Asn Met Leu Thr Ile Lys Ala Leu His Val Ala Pro Thr 1555 1560 1565 Thr Asn Leu Gly Gly Pro Glu Cys Cys Leu Arg Val Ser Leu Met Pro 1570 1575 1580 Leu Arg Leu Asn Val Asp Gln Asp Ala Leu Phe Phe Leu Lys Asp Phe 1585 1590 1595 1600 Phe Thr Ser Leu Val Ala Gly Ile Asn Pro Val Val Pro Gly Glu Thr 1605 1610 1615 Ser Ala Glu Ala Arg Pro Glu Thr Arg Ala Gln Pro Ser Ser Pro Leu 1620 1625 1630 Glu Gly Gln Ala Glu Gly Val Glu Thr Thr Gly Ser Gln Glu Ala Pro 1635 1640 1645 Gly Gly Gly His Ser Pro Ser Pro Pro Asp Gln Gln Pro Ile Tyr Phe 1650 1655 1660 Arg Glu Phe Arg Phe Thr Ser Glu Val Pro Ile Trp Leu Asp Tyr His 1665 1670 1675 1680 Gly Lys His Val Thr Met Asp Gln Val Gly Thr Phe Ala Gly Leu Leu 1685 1690 1695 Ile Gly Leu Ala Gln Leu Asn Cys Ser Glu Leu Lys Leu Lys Arg Leu 1700 1705 1710 Cys Cys Arg His Gly Leu Leu Gly Val Asp Lys Val Leu Gly Tyr Ala 1715 1720 1725 Leu Asn Glu Trp Leu Gln Asp Ile Arg Lys Asn Gln Leu Pro Gly Leu 1730 1735 1740 Leu Gly Gly Val Gly Pro Met His Ser Val Val Gln Leu Phe Gln Gly 1745 1750 1755 1760 Phe Arg Asp Leu Leu Trp Leu Pro Ile Glu Gln Tyr Arg Lys Asp Gly 1765 1770 1775 Arg Leu Met Arg Gly Leu Gln Arg Gly Ala Ala Ser Phe Gly Ser Ser 1780 1785 1790 Thr Ala Ser Ala Ala Leu Glu Leu Ser Asn Arg Leu Val Gln Ala Ile 1795 1800 1805 Gln Ala Thr Ala Glu Thr Val Tyr Asp Ile Leu Ser Pro Ala Ala Pro 1810 1815 1820 Val Ser Arg Ser Leu Gln Asp Lys Arg Ser Ala Arg Arg Leu Arg Arg 1825 1830 1835 1840 Gly Gln Gln Pro Ala Asp Leu Arg Glu Gly Val Ala Lys Ala Tyr Asp 1845 1850 1855 Thr Val Arg Glu Gly Ile Leu Asp Thr Ala Gln Thr Ile Cys Asp Val 1860 1865 1870 Ala Ser Arg Gly His Glu Gln Lys Gly Leu Thr Gly Ala Val Gly Gly 1875 1880 1885 Val Ile Arg Gln Leu Pro Pro Thr Val Val Lys Pro Leu Ile Leu Ala 1890 1895 1900 Thr Glu Ala Thr Ser Ser Leu Leu Gly Gly Met Arg Asn Gln Ile Val 1905 1910 1915 1920 Pro Asp Ala His Lys Asp His Ala Leu Lys Trp Arg Ser Asp Ser Ala 1925 1930 1935 Gln Asp <210> 3 <211> 1218 <212> PRT <213> Homo sapiens <400> 3 Met Glu Glu Asn Ser Lys Lys Asp His Arg Ala Leu Leu Asn Gln Gly 1 5 10 15 Glu Glu Asp Glu Leu Glu Val Phe Gly Tyr Arg Asp His Asn Val Arg 20 25 30 Lys Ala Phe Cys Leu Val Ala Ser Val Leu Thr Cys Gly Gly Leu Leu 35 40 45 Leu Val Phe Tyr Trp Arg Pro Gln Trp Arg Val Trp Ala Asn Cys Ile 50 55 60 Pro Cys Pro Leu Gln Glu Ala Asp Thr Val Leu Leu Arg Thr Thr Asp 65 70 75 80 Glu Phe Gln Arg Tyr Met Arg Lys Lys Val Phe Cys Leu Tyr Leu Ser 85 90 95 Thr Leu Lys Phe Pro Val Ser Lys Lys Trp Glu Glu Ser Leu Val Ala 100 105 110 Asp Arg His Ser Val Ile Asn Gln Ala Leu Ile Lys Pro Glu Leu Lys 115 120 125 Leu Arg Cys Met Glu Val Gln Lys Ile Arg Tyr Val Trp Asn Asp Leu 130 135 140 Glu Lys Arg Phe Gln Lys Val Gly Leu Leu Glu Asp Ser Asn Ser Cys 145 150 155 160 Ser Asp Ile His Gln Thr Phe Gly Leu Gly Leu Thr Ser Glu Glu Gln 165 170 175 Glu Val Arg Arg Leu Val Cys Gly Pro Asn Ala Ile Glu Val Glu Ile 180 185 190 Gln Pro Ile Trp Lys Leu Leu Val Lys Gln Val Leu Asn Pro Phe Tyr 195 200 205 Val Phe Gln Ala Phe Thr Leu Thr Leu Trp Leu Ser Gln Gly Tyr Ile 210 215 220 Glu Tyr Ser Val Ala Ile Ile Ile Leu Thr Val Ile Ser Ile Val Leu 225 230 235 240 Ser Val Tyr Asp Leu Arg Gln Gln Ser Val Lys Leu His Asn Leu Val 245 250 255 Glu Asp His Asn Lys Val Gln Val Thr Ile Ile Val Lys Asp Lys Gly 260 265 270 Leu Glu Glu Leu Glu Ser Arg Leu Leu Val Pro Gly Asp Ile Leu Ile 275 280 285 Leu Pro Gly Lys Phe Ser Leu Pro Cys Asp Ala Val Leu Ile Asp Gly 290 295 300 Ser Cys Val Val Asn Glu Gly Met Leu Thr Gly Glu Ser Ile Pro Val 305 310 315 320 Thr Lys Thr Pro Leu Pro Gln Met Glu Asn Thr Met Pro Trp Lys Cys 325 330 335 His Ser Leu Glu Asp Tyr Arg Lys His Val Leu Phe Cys Gly Thr Glu 340 345 350 Val Ile Gln Val Lys Pro Ser Gly Gln Gly Pro Val Arg Ala Val Val 355 360 365 Leu Gln Thr Gly Tyr Asn Thr Ala Lys Gly Asp Leu Val Arg Ser Ile 370 375 380 Leu Tyr Pro Arg Pro Leu Asn Phe Lys Leu Tyr Ser Asp Ala Phe Lys 385 390 395 400 Phe Ile Val Phe Leu Ala Cys Leu Gly Val Met Gly Phe Phe Tyr Ala 405 410 415 Leu Gly Val Tyr Met Tyr His Gly Val Pro Pro Lys Asp Thr Val Thr 420 425 430 Met Ala Leu Ile Leu Leu Thr Val Thr Val Pro Pro Val Leu Pro Ala 435 440 445 Ala Leu Thr Ile Gly Asn Val Tyr Ala Gln Lys Arg Leu Lys Lys Lys 450 455 460 Lys Ile Phe Cys Ile Ser Pro Gln Arg Ile Asn Met Cys Gly Gln Ile 465 470 475 480 Asn Leu Val Cys Phe Asp Lys Thr Gly Thr Leu Thr Glu Asp Gly Leu 485 490 495 Asp Leu Trp Gly Thr Val Pro Thr Ala Asp Asn Cys Phe Gln Glu Ala 500 505 510 His Ser Phe Ala Ser Gly Gln Ala Val Pro Trp Ser Pro Leu Cys Ala 515 520 525 Ala Met Ala Ser Cys His Ser Leu Ile Leu Leu Asn Gly Thr Ile Gln 530 535 540 Gly Asp Pro Leu Asp Leu Lys Met Phe Glu Gly Thr Ala Trp Lys Met 545 550 555 560 Glu Asp Cys Ile Val Asp Ser Cys Lys Phe Gly Thr Ser Val Ser Asn 565 570 575 Ile Ile Lys Pro Gly Pro Lys Ala Ser Lys Ser Pro Val Glu Ala Ile 580 585 590 Ile Thr Leu Cys Gln Phe Pro Phe Ser Ser Ser Leu Gln Arg Met Ser 595 600 605 Val Ile Ala Gln Leu Ala Gly Glu Asn His Phe His Val Tyr Met Lys 610 615 620 Gly Ala Pro Glu Met Val Ala Arg Phe Cys Arg Ser Glu Thr Val Pro 625 630 635 640 Lys Asn Phe Pro Gln Glu Leu Arg Ser Tyr Thr Val Gln Gly Phe Arg 645 650 655 Val Ile Ala Leu Ala His Lys Thr Leu Lys Met Gly Asn Leu Ser Glu 660 665 670 Val Glu His Leu Ala Arg Glu Lys Val Glu Ser Glu Leu Thr Phe Leu 675 680 685 Gly Leu Leu Ile Met Glu Asn Arg Leu Lys Lys Glu Thr Lys Leu Val 690 695 700 Leu Lys Glu Leu Ser Glu Ala Arg Ile Arg Thr Val Met Ile Thr Gly 705 710 715 720 Asp Asn Leu Gln Thr Ala Ile Thr Val Ala Lys Asn Ser Glu Met Ile 725 730 735 Pro Pro Gly Ser Gln Val Ile Ile Val Glu Ala Asp Glu Pro Glu Glu 740 745 750 Phe Val Pro Ala Ser Val Thr Trp Gln Leu Val Glu Asn Gln Glu Thr 755 760 765 Gly Pro Gly Lys Lys Glu Ile Tyr Met His Thr Gly Asn Ser Ser Thr 770 775 780 Pro Arg Gly Glu Gly Gly Ser Cys Tyr His Phe Ala Met Ser Gly Lys 785 790 795 800 Ser Tyr Gln Val Ile Phe Gln His Phe Asn Ser Leu Leu Pro Lys Ile 805 810 815 Leu Val Asn Gly Thr Val Phe Ala Arg Met Ser Pro Gly Gln Lys Ser 820 825 830 Ser Leu Ile Glu Glu Phe Gln Lys Leu Asn Tyr Tyr Val Gly Met Cys 835 840 845 Gly Asp Gly Ala Asn Asp Cys Gly Ala Leu Lys Ala Ala His Ala Gly 850 855 860 Ile Ser Leu Ser Glu Gln Glu Ala Ser Val Ala Ser Pro Phe Thr Ser 865 870 875 880 Lys Thr Thr Asn Ile Gln Cys Val Pro His Leu Ile Arg Glu Gly Arg 885 890 895 Ala Ala Leu Val Ser Ser Phe Gly Val Phe Lys Tyr Leu Thr Met Tyr 900 905 910 Gly Ile Ile Gln Phe Ile Ser Ala Leu Leu Leu Tyr Trp Gln Leu Gln 915 920 925 Leu Phe Gly Asn Tyr Gln Tyr Leu Met Gln Asp Val Ala Ile Thr Leu 930 935 940 Met Val Cys Leu Thr Met Ser Ser Thr His Ala Tyr Pro Lys Leu Ala 945 950 955 960 Pro Tyr Arg Pro Ala Gly Gln Leu Leu Ser Pro Pro Leu Leu Leu Ser 965 970 975 Ile Phe Leu Asn Ser Cys Phe Ser Cys Ile Val Gln Ile Ser Ala Phe 980 985 990 Leu Tyr Val Lys Gln Gln Pro Trp Tyr Cys Glu Val Tyr Gln Tyr Ser 995 1000 1005 Glu Cys Phe Leu Ala Asn Gln Ser Asn Phe Ser Thr Asn Val Ser Leu 1010 1015 1020 Glu Arg Asn Trp Thr Gly Asn Ala Thr Leu Ile Pro Gly Ser Ile Leu 1025 1030 1035 1040 Ser Phe Glu Thr Thr Thr Leu Trp Pro Ile Thr Thr Ile Asn Tyr Ile 1045 1050 1055 Thr Val Ala Phe Ile Phe Ser Lys Gly Lys Pro Phe Arg Lys Pro Ile 1060 1065 1070 Tyr Thr Asn Tyr Ile Phe Ser Phe Leu Leu Leu Ala Ala Leu Gly Leu 1075 1080 1085 Thr Ile Phe Ile Leu Phe Ser Asp Phe Gln Val Ile Tyr Arg Gly Met 1090 1095 1100 Glu Leu Ile Pro Thr Ile Thr Ser Trp Arg Val Leu Ile Leu Val Val 1105 1110 1115 1120 Ala Leu Thr Gln Phe Cys Val Ala Phe Phe Val Glu Asp Ser Ile Leu 1125 1130 1135 Gln Asn His Glu Leu Trp Leu Leu Ile Lys Arg Glu Phe Gly Phe Tyr 1140 1145 1150 Ser Lys Ser Gln Tyr Arg Thr Trp Gln Lys Lys Leu Ala Glu Asp Ser 1155 1160 1165 Thr Trp Pro Pro Ile Asn Arg Thr Asp Tyr Ser Gly Asp Gly Lys Asn 1170 1175 1180 Gly Phe Tyr Ile Asn Gly Gly Tyr Glu Ser His Glu Gln Ile Pro Lys 1185 1190 1195 1200 Arg Lys Leu Lys Leu Gly Gly Gln Pro Thr Glu Gln His Phe Trp Ala 1205 1210 1215 Arg Leu <210> 4 <211> 328 <212> PRT <213> Homo sapiens <400> 4 Met Thr Val Glu Lys Glu Ala Pro Asp Ala His Phe Thr Val Asp Lys 1 5 10 15 Gln Asn Ile Ser Leu Trp Pro Arg Glu Pro Pro Pro Lys Ser Gly Pro 20 25 30 Ser Leu Val Pro Gly Lys Thr Pro Thr Val Arg Ala Ala Leu Ile Cys 35 40 45 Leu Thr Leu Val Leu Val Ala Ser Val Leu Leu Gln Ala Val Leu Tyr 50 55 60 Pro Arg Phe Met Gly Thr Ile Ser Asp Val Lys Thr Asn Val Gln Leu 65 70 75 80 Leu Lys Gly Arg Val Asp Asn Ile Ser Thr Leu Asp Ser Glu Ile Lys 85 90 95 Lys Asn Ser Asp Gly Met Glu Ala Ala Gly Val Gln Ile Gln Met Val 100 105 110 Asn Glu Ser Leu Gly Tyr Val Arg Ser Gln Phe Leu Lys Leu Lys Thr 115 120 125 Ser Val Glu Lys Ala Asn Ala Gln Ile Gln Ile Leu Thr Arg Ser Trp 130 135 140 Glu Glu Val Ser Thr Leu Asn Ala Gln Ile Pro Glu Leu Lys Ser Asp 145 150 155 160 Leu Glu Lys Ala Ser Ala Leu Asn Thr Lys Ile Arg Ala Leu Gln Gly 165 170 175 Ser Leu Glu Asn Met Ser Lys Leu Leu Lys Arg Gln Asn Asp Ile Leu 180 185 190 Gln Val Val Ser Gln Gly Trp Lys Tyr Phe Lys Gly Asn Phe Tyr Tyr 195 200 205 Phe Ser Leu Ile Pro Lys Thr Trp Tyr Ser Ala Glu Gln Phe Cys Val 210 215 220 Ser Arg Asn Ser His Leu Thr Ser Val Thr Ser Glu Ser Glu Gln Glu 225 230 235 240 Phe Leu Tyr Lys Thr Ala Gly Gly Leu Ile Tyr Trp Ile Gly Leu Thr 245 250 255 Lys Ala Gly Met Glu Gly Asp Trp Ser Trp Val Asp Asp Thr Pro Phe 260 265 270 Asn Lys Val Gln Ser Val Arg Phe Trp Ile Pro Gly Glu Pro Asn Asn 275 280 285 Ala Gly Asn Asn Glu His Cys Gly Asn Ile Lys Ala Pro Ser Leu Gln 290 295 300 Ala Trp Asn Asp Ala Pro Cys Asp Lys Thr Phe Leu Phe Ile Cys Lys 305 310 315 320 Arg Pro Tyr Val Pro Ser Glu Pro 325 <210> 5 <211> 957 <212> PRT <213> Homo sapiens <400> 5 Met Ala His Tyr Ile Thr Phe Leu Cys Met Val Leu Val Leu Leu Leu 1 5 10 15 Gln Asn Ser Val Leu Ala Glu Asp Gly Glu Val Arg Ser Ser Cys Arg 20 25 30 Thr Ala Pro Thr Asp Leu Val Phe Ile Leu Asp Gly Ser Tyr Ser Val 35 40 45 Gly Pro Glu Asn Phe Glu Ile Val Lys Lys Trp Leu Val Asn Ile Thr 50 55 60 Lys Asn Phe Asp Ile Gly Pro Lys Phe Ile Gln Val Gly Val Val Gln 65 70 75 80 Tyr Ser Asp Tyr Pro Val Leu Glu Ile Pro Leu Gly Ser Tyr Asp Ser 85 90 95 Gly Glu His Leu Thr Ala Ala Val Glu Ser Ile Leu Tyr Leu Gly Gly 100 105 110 Asn Thr Lys Thr Gly Lys Ala Ile Gln Phe Ala Leu Asp Tyr Leu Phe 115 120 125 Ala Lys Ser Ser Arg Phe Leu Thr Lys Ile Ala Val Val Leu Thr Asp 130 135 140 Gly Lys Ser Gln Asp Asp Val Lys Asp Ala Ala Gln Ala Ala Arg Asp 145 150 155 160 Ser Lys Ile Thr Leu Phe Ala Ile Gly Val Gly Ser Glu Thr Glu Asp 165 170 175 Ala Glu Leu Arg Ala Ile Ala Asn Lys Pro Ser Ser Thr Tyr Val Phe 180 185 190 Tyr Val Glu Asp Tyr Ile Ala Ile Ser Lys Ile Arg Glu Val Met Lys 195 200 205 Gln Lys Leu Cys Glu Glu Ser Val Cys Pro Thr Arg Ile Pro Val Ala 210 215 220 Ala Arg Asp Glu Arg Gly Phe Asp Ile Leu Leu Gly Leu Asp Val Asn 225 230 235 240 Lys Lys Val Lys Lys Arg Ile Gln Leu Ser Pro Lys Lys Ile Lys Gly 245 250 255 Tyr Glu Val Thr Ser Lys Val Asp Leu Ser Glu Leu Thr Ser Asn Val 260 265 270 Phe Pro Glu Gly Leu Pro Pro Ser Tyr Val Phe Val Ser Thr Gln Arg 275 280 285 Phe Lys Val Lys Lys Ile Trp Asp Leu Trp Arg Ile Leu Thr Ile Asp 290 295 300 Gly Arg Pro Gln Ile Ala Val Thr Leu Asn Gly Val Asp Lys Ile Leu 305 310 315 320 Leu Phe Thr Thr Thr Ser Val Ile Asn Gly Ser Gln Val Val Thr Phe 325 330 335 Ala Asn Pro Gln Val Lys Thr Leu Phe Asp Glu Gly Trp His Gln Ile 340 345 350 Arg Leu Leu Val Thr Glu Gln Asp Val Thr Leu Tyr Ile Asp Asp Gln 355 360 365 Gln Ile Glu Asn Lys Pro Leu His Pro Val Leu Gly Ile Leu Ile Asn 370 375 380 Gly Gln Thr Gln Ile Gly Lys Tyr Ser Gly Lys Glu Glu Thr Val Gln 385 390 395 400 Phe Asp Val Gln Lys Leu Arg Ile Tyr Cys Asp Pro Glu Gln Asn Asn 405 410 415 Arg Glu Thr Ala Cys Glu Ile Pro Gly Phe Asn Gly Glu Cys Leu Asn 420 425 430 Gly Pro Ser Asp Val Gly Ser Thr Pro Ala Pro Cys Ile Cys Pro Pro 435 440 445 Gly Lys Pro Gly Leu Gln Gly Pro Lys Gly Asp Pro Gly Leu Pro Gly 450 455 460 Asn Pro Gly Tyr Pro Gly Gln Pro Gly Gln Asp Gly Lys Pro Gly Tyr 465 470 475 480 Gln Gly Ile Ala Gly Thr Pro Gly Val Pro Gly Ser Pro Gly Ile Gln 485 490 495 Gly Ala Arg Gly Leu Pro Gly Tyr Lys Gly Glu Pro Gly Arg Asp Gly 500 505 510 Asp Lys Gly Asp Arg Gly Leu Pro Gly Phe Pro Gly Leu His Gly Met 515 520 525 Pro Gly Ser Lys Gly Glu Met Gly Ala Lys Gly Asp Lys Gly Ser Pro 530 535 540 Gly Phe Tyr Gly Lys Lys Gly Ala Lys Gly Glu Lys Gly Asn Ala Gly 545 550 555 560 Phe Pro Gly Leu Pro Gly Pro Ala Gly Glu Pro Gly Arg His Gly Lys 565 570 575 Asp Gly Leu Met Gly Ser Pro Gly Phe Lys Gly Glu Ala Gly Ser Pro 580 585 590 Gly Ala Pro Gly Gln Asp Gly Thr Arg Gly Glu Pro Gly Ile Pro Gly 595 600 605 Phe Pro Gly Asn Arg Gly Leu Met Gly Gln Lys Gly Glu Ile Gly Pro 610 615 620 Pro Gly Gln Gln Gly Lys Lys Gly Ala Pro Gly Met Pro Gly Leu Met 625 630 635 640 Gly Ser Asn Gly Ser Pro Gly Gln Pro Gly Thr Pro Gly Ser Lys Gly 645 650 655 Ser Lys Gly Glu Pro Gly Ile Gln Gly Met Pro Gly Ala Ser Gly Leu 660 665 670 Lys Gly Glu Pro Gly Ala Thr Gly Ser Pro Gly Glu Pro Gly Tyr Met 675 680 685 Gly Leu Pro Gly Ile Gln Gly Lys Lys Gly Asp Lys Gly Asn Gln Gly 690 695 700 Glu Lys Gly Ile Gln Gly Gln Lys Gly Glu Asn Gly Arg Gln Gly Ile 705 710 715 720 Pro Gly Gln Gln Gly Ile Gln Gly His His Gly Ala Lys Gly Glu Arg 725 730 735 Gly Glu Lys Gly Glu Pro Gly Val Arg Gly Ala Ile Gly Ser Lys Gly 740 745 750 Glu Ser Gly Val Asp Gly Leu Met Gly Pro Ala Gly Pro Lys Gly Gln 755 760 765 Pro Gly Asp Pro Gly Pro Gln Gly Pro Pro Gly Leu Asp Gly Lys Pro 770 775 780 Gly Arg Glu Phe Ser Glu Gln Phe Ile Arg Gln Val Cys Thr Asp Val 785 790 795 800 Ile Arg Ala Gln Leu Pro Val Leu Leu Gln Ser Gly Arg Ile Arg Asn 805 810 815 Cys Asp His Cys Leu Ser Gln His Gly Ser Pro Gly Ile Pro Gly Pro 820 825 830 Pro Gly Pro Ile Gly Pro Glu Gly Pro Arg Gly Leu Pro Gly Leu Pro 835 840 845 Gly Arg Asp Gly Val Pro Gly Leu Val Gly Val Pro Gly Arg Pro Gly 850 855 860 Val Arg Gly Leu Lys Gly Leu Pro Gly Arg Asn Gly Glu Lys Gly Ser 865 870 875 880 Gln Gly Phe Gly Tyr Pro Gly Glu Gln Gly Pro Pro Gly Pro Pro Gly 885 890 895 Pro Glu Gly Pro Pro Gly Ile Ser Lys Glu Gly Pro Pro Gly Asp Pro 900 905 910 Gly Leu Pro Gly Lys Asp Gly Asp His Gly Lys Pro Gly Ile Gln Gly 915 920 925 Gln Pro Gly Pro Pro Gly Ile Cys Asp Pro Ser Leu Cys Phe Ser Val 930 935 940 Ile Ala Arg Arg Asp Pro Phe Arg Lys Gly Pro Asn Tyr 945 950 955 <210> 6 <211> 734 <212> PRT <213> Homo sapiens <400> 6 Met Trp Gly Leu Leu Leu Ala Leu Ala Ala Phe Ala Pro Ala Val Gly 1 5 10 15 Pro Ala Leu Gly Ala Pro Arg Asn Ser Val Leu Gly Leu Ala Gln Pro 20 25 30 Gly Thr Thr Lys Val Pro Gly Ser Thr Pro Ala Leu His Ser Ser Pro 35 40 45 Ala Gln Pro Pro Ala Glu Thr Ala Asn Gly Thr Ser Glu Gln His Val 50 55 60 Arg Ile Arg Val Ile Lys Lys Lys Lys Val Ile Met Lys Lys Arg Lys 65 70 75 80 Lys Leu Thr Leu Thr Arg Pro Thr Pro Leu Val Thr Ala Gly Pro Leu 85 90 95 Val Thr Pro Thr Pro Ala Gly Thr Leu Asp Pro Ala Glu Lys Gln Glu 100 105 110 Thr Gly Cys Pro Pro Leu Gly Leu Glu Ser Leu Arg Val Ser Asp Ser 115 120 125 Arg Leu Glu Ala Ser Ser Ser Gln Ser Phe Gly Leu Gly Pro His Arg 130 135 140 Gly Arg Leu Asn Ile Gln Ser Gly Leu Glu Asp Gly Asp Leu Tyr Asp 145 150 155 160 Gly Ala Trp Cys Ala Glu Glu Gln Asp Ala Asp Pro Trp Phe Gln Val 165 170 175 Asp Ala Gly His Pro Thr Arg Phe Ser Gly Val Ile Thr Gln Gly Arg 180 185 190 Asn Ser Val Trp Arg Tyr Asp Trp Val Thr Ser Tyr Lys Val Gln Phe 195 200 205 Ser Asn Asp Ser Arg Thr Trp Trp Gly Ser Arg Asn His Ser Ser Gly 210 215 220 Met Asp Ala Val Phe Pro Ala Asn Ser Asp Pro Glu Thr Pro Val Leu 225 230 235 240 Asn Leu Leu Pro Glu Pro Gln Val Ala Arg Phe Ile Arg Leu Leu Pro 245 250 255 Gln Thr Trp Leu Gln Gly Gly Ala Pro Cys Leu Arg Ala Glu Ile Leu 260 265 270 Ala Cys Pro Val Ser Asp Pro Asn Asp Leu Phe Leu Glu Ala Pro Ala 275 280 285 Ser Gly Ser Ser Asp Pro Leu Asp Phe Gln His His Asn Tyr Lys Ala 290 295 300 Met Arg Lys Leu Met Lys Gln Val Gln Glu Gln Cys Pro Asn Ile Thr 305 310 315 320 Arg Ile Tyr Ser Ile Gly Lys Ser Tyr Gln Gly Leu Lys Leu Tyr Val 325 330 335 Met Glu Met Ser Asp Lys Pro Gly Glu His Glu Leu Gly Glu Pro Glu 340 345 350 Val Arg Tyr Val Ala Gly Met His Gly Asn Glu Ala Leu Gly Arg Glu 355 360 365 Leu Leu Leu Leu Leu Met Gln Phe Leu Cys His Glu Phe Leu Arg Gly 370 375 380 Asn Pro Arg Val Thr Arg Leu Leu Ser Glu Met Arg Ile His Leu Leu 385 390 395 400 Pro Ser Met Asn Pro Asp Gly Tyr Glu Ile Ala Tyr His Arg Gly Ser 405 410 415 Glu Leu Val Gly Trp Ala Glu Gly Arg Trp Asn Asn Gln Ser Ile Asp 420 425 430 Leu Asn His Asn Phe Ala Asp Leu Asn Thr Pro Leu Trp Glu Ala Gln 435 440 445 Asp Asp Gly Lys Val Pro His Ile Val Pro Asn His His Leu Pro Leu 450 455 460 Pro Thr Tyr Tyr Thr Leu Pro Asn Ala Thr Val Ala Pro Glu Thr Arg 465 470 475 480 Ala Val Ile Lys Trp Met Lys Arg Ile Pro Phe Val Leu Ser Ala Asn 485 490 495 Leu His Gly Gly Glu Leu Val Val Ser Tyr Pro Phe Asp Met Thr Arg 500 505 510 Thr Pro Trp Ala Ala Arg Glu Leu Thr Pro Thr Pro Asp Asp Ala Val 515 520 525 Phe Arg Trp Leu Ser Thr Val Tyr Ala Gly Ser Asn Leu Ala Met Gln 530 535 540 Asp Thr Ser Arg Arg Pro Cys His Ser Gln Asp Phe Ser Val His Gly 545 550 555 560 Asn Ile Ile Asn Gly Ala Asp Trp His Thr Val Pro Gly Ser Met Asn 565 570 575 Asp Phe Ser Tyr Leu His Thr Asn Cys Phe Glu Val Thr Val Glu Leu 580 585 590 Ser Cys Asp Lys Phe Pro His Glu Asn Glu Leu Pro Gln Glu Trp Glu 595 600 605 Asn Asn Lys Asp Ala Leu Leu Thr Tyr Leu Glu Gln Val Arg Met Gly 610 615 620 Ile Ala Gly Val Val Arg Asp Lys Asp Thr Glu Leu Gly Ile Ala Asp 625 630 635 640 Ala Val Ile Ala Val Asp Gly Ile Asn His Asp Val Thr Thr Ala Trp 645 650 655 Gly Gly Asp Tyr Trp Arg Leu Leu Thr Pro Gly Asp Tyr Met Val Thr 660 665 670 Ala Ser Ala Glu Gly Tyr His Ser Val Thr Arg Asn Cys Arg Val Thr 675 680 685 Phe Glu Glu Gly Pro Phe Pro Cys Asn Phe Val Leu Thr Lys Thr Pro 690 695 700 Lys Gln Arg Leu Arg Glu Leu Leu Ala Ala Gly Ala Lys Val Pro Pro 705 710 715 720 Asp Leu Arg Arg Arg Leu Glu Arg Leu Arg Gly Gln Lys Asp 725 730 <210> 7 <211> 466 <212> PRT <213> Homo sapiens <400> 7 Met Ala Leu Leu Thr Ala Ala Ala Arg Leu Leu Gly Thr Lys Asn Ala 1 5 10 15 Ser Cys Leu Val Leu Ala Ala Arg His Ala Ser Ala Ser Ser Thr Asn 20 25 30 Leu Lys Asp Ile Leu Ala Asp Leu Ile Pro Lys Glu Gln Ala Arg Ile 35 40 45 Lys Thr Phe Arg Gln Gln His Gly Lys Thr Val Val Gly Gln Ile Thr 50 55 60 Val Asp Met Met Tyr Gly Gly Met Arg Gly Met Lys Gly Leu Val Tyr 65 70 75 80 Glu Thr Ser Val Leu Asp Pro Asp Glu Gly Ile Arg Phe Arg Gly Phe 85 90 95 Ser Ile Pro Glu Cys Gln Lys Leu Leu Pro Lys Ala Lys Gly Gly Glu 100 105 110 Glu Pro Leu Pro Glu Gly Leu Phe Trp Leu Leu Val Thr Gly His Ile 115 120 125 Pro Thr Glu Glu Gln Val Ser Trp Leu Ser Lys Glu Trp Ala Lys Arg 130 135 140 Ala Ala Leu Pro Ser His Val Val Thr Met Leu Asp Asn Phe Pro Thr 145 150 155 160 Asn Leu His Pro Met Ser Gln Leu Ser Ala Ala Val Thr Ala Leu Asn 165 170 175 Ser Glu Ser Asn Phe Ala Arg Ala Tyr Ala Gln Gly Ile Ser Arg Thr 180 185 190 Lys Tyr Trp Glu Leu Ile Tyr Glu Asp Ser Met Asp Leu Ile Ala Lys 195 200 205 Leu Pro Cys Val Ala Ala Lys Ile Tyr Arg Asn Leu Tyr Arg Glu Gly 210 215 220 Ser Gly Ile Gly Ala Ile Asp Ser Asn Leu Asp Trp Ser His Asn Phe 225 230 235 240 Thr Asn Met Leu Gly Tyr Thr Asp His Gln Phe Thr Glu Leu Thr Arg 245 250 255 Leu Tyr Leu Thr Ile His Ser Asp His Glu Gly Gly Asn Val Ser Ala 260 265 270 His Thr Ser His Leu Val Gly Ser Ala Leu Ser Asp Pro Tyr Leu Ser 275 280 285 Phe Ala Ala Ala Met Asn Gly Leu Ala Gly Pro Leu His Gly Leu Ala 290 295 300 Asn Gln Glu Val Leu Val Trp Leu Thr Gln Leu Gln Lys Glu Val Gly 305 310 315 320 Lys Asp Val Ser Asp Glu Lys Leu Arg Asp Tyr Ile Trp Asn Thr Leu 325 330 335 Asn Ser Gly Arg Val Val Pro Gly Tyr Gly His Ala Val Leu Arg Lys 340 345 350 Thr Asp Pro Arg Tyr Thr Cys Gln Arg Glu Phe Ala Leu Lys His Leu 355 360 365 Pro Asn Asp Pro Met Phe Lys Leu Val Ala Gln Leu Tyr Lys Ile Val 370 375 380 Pro Asn Val Leu Leu Glu Gln Gly Lys Ala Lys Asn Pro Trp Pro Asn 385 390 395 400 Val Asp Ala His Ser Gly Val Leu Leu Gln Tyr Tyr Gly Met Thr Glu 405 410 415 Met Asn Tyr Tyr Thr Val Leu Phe Gly Val Ser Arg Ala Leu Gly Val 420 425 430 Leu Ala Gln Leu Ile Trp Ser Arg Ala Leu Gly Phe Pro Leu Glu Arg 435 440 445 Pro Lys Ser Met Ser Thr Glu Gly Leu Met Lys Phe Val Asp Ser Lys 450 455 460 Ser Gly 465 <210> 8 <211> 396 <212> PRT <213> Homo sapiens <400> 8 Met Lys Thr Leu Leu Leu Leu Leu Leu Val Leu Leu Glu Leu Gly Glu 1 5 10 15 Ala Gln Gly Ser Leu His Arg Val Pro Leu Arg Arg His Pro Ser Leu 20 25 30 Lys Lys Lys Leu Arg Ala Arg Ser Gln Leu Ser Glu Phe Trp Lys Ser 35 40 45 His Asn Leu Asp Met Ile Gln Phe Thr Glu Ser Cys Ser Met Asp Gln 50 55 60 Ser Ala Lys Glu Pro Leu Ile Asn Tyr Leu Asp Met Glu Tyr Phe Gly 65 70 75 80 Thr Ile Ser Ile Gly Ser Pro Pro Gln Asn Phe Thr Val Ile Phe Asp 85 90 95 Thr Gly Ser Ser Asn Leu Trp Val Pro Ser Val Tyr Cys Thr Ser Pro 100 105 110 Ala Cys Lys Thr His Ser Arg Phe Gln Pro Ser Gln Ser Ser Thr Tyr 115 120 125 Ser Gln Pro Gly Gln Ser Phe Ser Ile Gln Tyr Gly Thr Gly Ser Leu 130 135 140 Ser Gly Ile Ile Gly Ala Asp Gln Val Ser Val Glu Gly Leu Thr Val 145 150 155 160 Val Gly Gln Gln Phe Gly Glu Ser Val Thr Glu Pro Gly Gln Thr Phe 165 170 175 Val Asp Ala Glu Phe Asp Gly Ile Leu Gly Leu Gly Tyr Pro Ser Leu 180 185 190 Ala Val Gly Gly Val Thr Pro Val Phe Asp Asn Met Met Ala Gln Asn 195 200 205 Leu Val Asp Leu Pro Met Phe Ser Val Tyr Met Ser Ser Asn Pro Glu 210 215 220 Gly Gly Ala Gly Ser Glu Leu Ile Phe Gly Gly Tyr Asp His Ser His 225 230 235 240 Phe Ser Gly Ser Leu Asn Trp Val Pro Val Thr Lys Gln Ala Tyr Trp 245 250 255 Gln Ile Ala Leu Asp Asn Ile Gln Val Gly Gly Thr Val Met Phe Cys 260 265 270 Ser Glu Gly Cys Gln Ala Ile Val Asp Thr Gly Thr Ser Leu Ile Thr 275 280 285 Gly Pro Ser Asp Lys Ile Lys Gln Leu Gln Asn Ala Ile Gly Ala Ala 290 295 300 Pro Val Asp Gly Glu Tyr Ala Val Glu Cys Ala Asn Leu Asn Val Met 305 310 315 320 Pro Asp Val Thr Phe Thr Ile Asn Gly Val Pro Tyr Thr Leu Ser Pro 325 330 335 Thr Ala Tyr Thr Leu Leu Asp Phe Val Asp Gly Met Gln Phe Cys Ser 340 345 350 Ser Gly Phe Gln Gly Leu Asp Ile His Pro Pro Ala Gly Pro Leu Trp 355 360 365 Ile Leu Gly Asp Val Phe Ile Arg Gln Phe Tyr Ser Val Phe Asp Arg 370 375 380 Gly Asn Asn Arg Val Gly Leu Ala Pro Ala Val Pro 385 390 395 <210> 9 <211> 429 <212> PRT <213> Homo sapiens <400> 9 Met Leu Pro Arg Leu Leu Leu Leu Ile Cys Ala Pro Leu Cys Glu Pro 1 5 10 15 Ala Glu Leu Phe Leu Ile Ala Ser Pro Ser His Pro Thr Glu Gly Ser 20 25 30 Pro Val Thr Leu Thr Cys Lys Met Pro Phe Leu Gln Ser Ser Asp Ala 35 40 45 Gln Phe Gln Phe Cys Phe Phe Arg Asp Thr Arg Ala Leu Gly Pro Gly 50 55 60 Trp Ser Ser Ser Pro Lys Leu Gln Ile Ala Ala Met Trp Lys Glu Asp 65 70 75 80 Thr Gly Ser Tyr Trp Cys Glu Ala Gln Thr Met Ala Ser Lys Val Leu 85 90 95 Arg Ser Arg Arg Ser Gln Ile Asn Val His Arg Val Pro Val Ala Asp 100 105 110 Val Ser Leu Glu Thr Gln Pro Pro Gly Gly Gln Val Met Glu Gly Asp 115 120 125 Arg Leu Val Leu Ile Cys Ser Val Ala Met Gly Thr Gly Asp Ile Thr 130 135 140 Phe Leu Trp Tyr Lys Gly Ala Val Gly Leu Asn Leu Gln Ser Lys Thr 145 150 155 160 Gln Arg Ser Leu Thr Ala Glu Tyr Glu Ile Pro Ser Val Arg Glu Ser 165 170 175 Asp Ala Glu Gln Tyr Tyr Cys Val Ala Glu Asn Gly Tyr Gly Pro Ser 180 185 190 Pro Ser Gly Leu Val Ser Ile Thr Val Arg Ile Pro Val Ser Arg Pro 195 200 205 Ile Leu Met Leu Arg Ala Pro Arg Ala Gln Ala Ala Val Glu Asp Val 210 215 220 Leu Glu Leu His Cys Glu Ala Leu Arg Gly Ser Pro Pro Ile Leu Tyr 225 230 235 240 Trp Phe Tyr His Glu Asp Ile Thr Leu Gly Ser Arg Ser Ala Pro Ser 245 250 255 Gly Gly Gly Ala Ser Phe Asn Leu Ser Leu Thr Glu Glu His Ser Gly 260 265 270 Asn Tyr Ser Cys Glu Ala Asn Asn Gly Leu Gly Ala Gln Arg Ser Glu 275 280 285 Ala Val Thr Leu Asn Phe Thr Val Pro Thr Gly Ala Arg Ser Asn His 290 295 300 Leu Thr Ser Gly Val Ile Glu Gly Leu Leu Ser Thr Leu Gly Pro Ala 305 310 315 320 Thr Val Ala Leu Leu Phe Cys Tyr Gly Leu Lys Arg Lys Ile Gly Arg 325 330 335 Arg Ser Ala Arg Asp Pro Leu Arg Ser Leu Pro Ser Pro Leu Pro Gln 340 345 350 Glu Phe Thr Tyr Leu Asn Ser Pro Thr Pro Gly Gln Leu Gln Pro Ile 355 360 365 Tyr Glu Asn Val Asn Val Val Ser Gly Asp Glu Val Tyr Ser Leu Ala 370 375 380 Tyr Tyr Asn Gln Pro Glu Gln Glu Ser Val Ala Ala Glu Thr Leu Gly 385 390 395 400 Thr His Met Glu Asp Lys Val Ser Leu Asp Ile Tyr Ser Arg Leu Arg 405 410 415 Lys Ala Asn Ile Thr Asp Val Asp Tyr Glu Asp Ala Met 420 425 <210> 10 <211> 620 <212> PRT <213> Homo sapiens <400> 10 Met Gln Val Ser Lys Arg Met Leu Ala Gly Gly Val Arg Ser Met Pro 1 5 10 15 Ser Pro Leu Leu Ala Cys Trp Gln Pro Ile Leu Leu Leu Val Leu Gly 20 25 30 Ser Val Leu Ser Gly Ser Ala Thr Gly Cys Pro Pro Arg Cys Glu Cys 35 40 45 Ser Ala Gln Asp Arg Ala Val Leu Cys His Arg Lys Arg Phe Val Ala 50 55 60 Val Pro Glu Gly Ile Pro Thr Glu Thr Arg Leu Leu Asp Leu Gly Lys 65 70 75 80 Asn Arg Ile Lys Thr Leu Asn Gln Asp Glu Phe Ala Ser Phe Pro His 85 90 95 Leu Glu Glu Leu Glu Leu Asn Glu Asn Ile Val Ser Ala Val Glu Pro 100 105 110 Gly Ala Phe Asn Asn Leu Phe Asn Leu Arg Thr Leu Gly Leu Arg Ser 115 120 125 Asn Arg Leu Lys Leu Ile Pro Leu Gly Val Phe Thr Gly Leu Ser Asn 130 135 140 Leu Thr Lys Leu Asp Ile Ser Glu Asn Lys Ile Val Ile Leu Leu Asp 145 150 155 160 Tyr Met Phe Gln Asp Leu Tyr Asn Leu Lys Ser Leu Glu Val Gly Asp 165 170 175 Asn Asp Leu Val Tyr Ile Ser His Arg Ala Phe Ser Gly Leu Asn Ser 180 185 190 Leu Glu Gln Leu Thr Leu Glu Lys Cys Asn Leu Thr Ser Ile Pro Thr 195 200 205 Glu Ala Leu Ser His Leu His Gly Leu Ile Val Leu Arg Leu Arg His 210 215 220 Leu Asn Ile Asn Ala Ile Arg Asp Tyr Ser Phe Lys Arg Leu Tyr Arg 225 230 235 240 Leu Lys Val Leu Glu Ile Ser His Trp Pro Tyr Leu Asp Thr Met Thr 245 250 255 Pro Asn Cys Leu Tyr Gly Leu Asn Leu Thr Ser Leu Ser Ile Thr His 260 265 270 Cys Asn Leu Thr Ala Val Pro Tyr Leu Ala Val Arg His Leu Val Tyr 275 280 285 Leu Arg Phe Leu Asn Leu Ser Tyr Asn Pro Ile Ser Thr Ile Glu Gly 290 295 300 Ser Met Leu His Glu Leu Leu Arg Leu Gln Glu Ile Gln Leu Val Gly 305 310 315 320 Gly Gln Leu Ala Val Val Glu Pro Tyr Ala Phe Arg Gly Leu Asn Tyr 325 330 335 Leu Arg Val Leu Asn Val Ser Gly Asn Gln Leu Thr Thr Leu Glu Glu 340 345 350 Ser Val Phe His Ser Val Gly Asn Leu Glu Thr Leu Ile Leu Asp Ser 355 360 365 Asn Pro Leu Ala Cys Asp Cys Arg Leu Leu Trp Val Phe Arg Arg Arg 370 375 380 Trp Arg Leu Asn Phe Asn Arg Gln Gln Pro Thr Cys Ala Thr Pro Glu 385 390 395 400 Phe Val Gln Gly Lys Glu Phe Lys Asp Phe Pro Asp Val Leu Leu Pro 405 410 415 Asn Tyr Phe Thr Cys Arg Arg Ala Arg Ile Arg Asp Arg Lys Ala Gln 420 425 430 Gln Val Phe Val Asp Glu Gly His Thr Val Gln Phe Val Cys Arg Ala 435 440 445 Asp Gly Asp Pro Pro Pro Ala Ile Leu Trp Leu Ser Pro Arg Lys His 450 455 460 Leu Val Ser Ala Lys Ser Asn Gly Arg Leu Thr Val Phe Pro Asp Gly 465 470 475 480 Thr Leu Glu Val Arg Tyr Ala Gln Val Gln Asp Asn Gly Thr Tyr Leu 485 490 495 Cys Ile Ala Ala Asn Ala Gly Gly Asn Asp Ser Met Pro Ala His Leu 500 505 510 His Val Arg Ser Tyr Ser Pro Asp Trp Pro His Gln Pro Asn Lys Thr 515 520 525 Phe Ala Phe Ile Ser Asn Gln Pro Gly Glu Gly Glu Ala Asn Ser Thr 530 535 540 Arg Ala Thr Val Pro Phe Pro Phe Asp Ile Lys Thr Leu Ile Ile Ala 545 550 555 560 Thr Thr Met Gly Phe Ile Ser Phe Leu Gly Val Val Leu Phe Cys Leu 565 570 575 Val Leu Leu Phe Leu Trp Ser Arg Gly Lys Gly Asn Thr Lys His Asn 580 585 590 Ile Glu Ile Glu Tyr Val Pro Arg Lys Ser Asp Ala Gly Ile Ser Ser 595 600 605 Ala Asp Ala Pro Arg Lys Phe Asn Met Lys Met Ile 610 615 620 <210> 11 <211> 1972 <212> PRT <213> Homo sapiens <400> 11 Met Ala Gln Lys Gly Gln Leu Ser Asp Asp Glu Lys Phe Leu Phe Val 1 5 10 15 Asp Lys Asn Phe Ile Asn Ser Pro Val Ala Gln Ala Asp Trp Ala Ala 20 25 30 Lys Arg Leu Val Trp Val Pro Ser Glu Lys Gln Gly Phe Glu Ala Ala 35 40 45 Ser Ile Lys Glu Glu Lys Gly Asp Glu Val Val Val Glu Leu Val Glu 50 55 60 Asn Gly Lys Lys Val Thr Val Gly Lys Asp Asp Ile Gln Lys Met Asn 65 70 75 80 Pro Pro Lys Phe Ser Lys Val Glu Asp Met Ala Glu Leu Thr Cys Leu 85 90 95 Asn Glu Ala Ser Val Leu His Asn Leu Arg Glu Arg Tyr Phe Ser Gly 100 105 110 Leu Ile Tyr Thr Tyr Ser Gly Leu Phe Cys Val Val Val Asn Pro Tyr 115 120 125 Lys His Leu Pro Ile Tyr Ser Glu Lys Ile Val Asp Met Tyr Lys Gly 130 135 140 Lys Lys Arg His Glu Met Pro Pro His Ile Tyr Ala Ile Ala Asp Thr 145 150 155 160 Ala Tyr Arg Ser Met Leu Gln Asp Arg Glu Asp Gln Ser Ile Leu Cys 165 170 175 Thr Gly Glu Ser Gly Ala Gly Lys Thr Glu Asn Thr Lys Lys Val Ile 180 185 190 Gln Tyr Leu Ala Val Val Ala Ser Ser His Lys Gly Lys Lys Asp Thr 195 200 205 Ser Ile Thr Gly Glu Leu Glu Lys Gln Leu Leu Gln Ala Asn Pro Ile 210 215 220 Leu Glu Ala Phe Gly Asn Ala Lys Thr Val Lys Asn Asp Asn Ser Ser 225 230 235 240 Arg Phe Gly Lys Phe Ile Arg Ile Asn Phe Asp Val Thr Gly Tyr Ile 245 250 255 Val Gly Ala Asn Ile Glu Thr Tyr Leu Leu Glu Lys Ser Arg Ala Ile 260 265 270 Arg Gln Ala Arg Asp Glu Arg Thr Phe His Ile Phe Tyr Tyr Met Ile 275 280 285 Ala Gly Ala Lys Glu Lys Met Arg Ser Asp Leu Leu Leu Glu Gly Phe 290 295 300 Asn Asn Tyr Thr Phe Leu Ser Asn Gly Phe Val Pro Ile Pro Ala Ala 305 310 315 320 Gln Asp Asp Glu Met Phe Gln Glu Thr Val Glu Ala Met Ala Ile Met 325 330 335 Gly Phe Ser Glu Glu Glu Gln Leu Ser Ile Leu Lys Val Val Ser Ser 340 345 350 Val Leu Gln Leu Gly Asn Ile Val Phe Lys Lys Glu Arg Asn Thr Asp 355 360 365 Gln Ala Ser Met Pro Asp Asn Thr Ala Ala Gln Lys Val Cys His Leu 370 375 380 Met Gly Ile Asn Val Thr Asp Phe Thr Arg Ser Ile Leu Thr Pro Arg 385 390 395 400 Ile Lys Val Gly Arg Asp Val Val Gln Lys Ala Gln Thr Lys Glu Gln 405 410 415 Ala Asp Phe Ala Val Glu Ala Leu Ala Lys Ala Thr Tyr Glu Arg Leu 420 425 430 Phe Arg Trp Ile Leu Thr Arg Val Asn Lys Ala Leu Asp Lys Thr His 435 440 445 Arg Gln Gly Ala Ser Phe Leu Gly Ile Leu Asp Ile Ala Gly Phe Glu 450 455 460 Ile Phe Glu Val Asn Ser Phe Glu Gln Leu Cys Ile Asn Tyr Thr Asn 465 470 475 480 Glu Lys Leu Gln Gln Leu Phe Asn His Thr Met Phe Ile Leu Glu Gln 485 490 495 Glu Glu Tyr Gln Arg Glu Gly Ile Glu Trp Asn Phe Ile Asp Phe Gly 500 505 510 Leu Asp Leu Gln Pro Cys Ile Glu Leu Ile Glu Arg Pro Asn Asn Pro 515 520 525 Pro Gly Val Leu Ala Leu Leu Asp Glu Glu Cys Trp Phe Pro Lys Ala 530 535 540 Thr Asp Lys Ser Phe Val Glu Lys Leu Cys Thr Glu Gln Gly Ser His 545 550 555 560 Pro Lys Phe Gln Lys Pro Lys Gln Leu Lys Asp Lys Thr Glu Phe Ser 565 570 575 Ile Ile His Tyr Ala Gly Lys Val Asp Tyr Asn Ala Ser Ala Trp Leu 580 585 590 Thr Lys Asn Met Asp Pro Leu Asn Asp Asn Val Thr Ser Leu Leu Asn 595 600 605 Ala Ser Ser Asp Lys Phe Val Ala Asp Leu Trp Lys Asp Val Asp Arg 610 615 620 Ile Val Gly Leu Asp Gln Met Ala Lys Met Thr Glu Ser Ser Leu Pro 625 630 635 640 Ser Ala Ser Lys Thr Lys Lys Gly Met Phe Arg Thr Val Gly Gln Leu 645 650 655 Tyr Lys Glu Gln Leu Gly Lys Leu Met Thr Thr Leu Arg Asn Thr Thr 660 665 670 Pro Asn Phe Val Arg Cys Ile Ile Pro Asn His Glu Lys Arg Ser Gly 675 680 685 Lys Leu Asp Ala Phe Leu Val Leu Glu Gln Leu Arg Cys Asn Gly Val 690 695 700 Leu Glu Gly Ile Arg Ile Cys Arg Gln Gly Phe Pro Asn Arg Ile Val 705 710 715 720 Phe Gln Glu Phe Arg Gln Arg Tyr Glu Ile Leu Ala Ala Asn Ala Ile 725 730 735 Pro Lys Gly Phe Met Asp Gly Lys Gln Ala Cys Ile Leu Met Ile Lys 740 745 750 Ala Leu Glu Leu Asp Pro Asn Leu Tyr Arg Ile Gly Gln Ser Lys Ile 755 760 765 Phe Phe Arg Thr Gly Val Leu Ala His Leu Glu Glu Glu Arg Asp Leu 770 775 780 Lys Ile Thr Asp Val Ile Met Ala Phe Gln Ala Met Cys Arg Gly Tyr 785 790 795 800 Leu Ala Arg Lys Ala Phe Ala Lys Arg Gln Gln Gln Leu Thr Ala Met 805 810 815 Lys Val Ile Gln Arg Asn Cys Ala Ala Tyr Leu Lys Leu Arg Asn Trp 820 825 830 Gln Trp Trp Arg Leu Phe Thr Lys Val Lys Pro Leu Leu Gln Val Thr 835 840 845 Arg Gln Glu Glu Glu Met Gln Ala Lys Glu Asp Glu Leu Gln Lys Thr 850 855 860 Lys Glu Arg Gln Gln Lys Ala Glu Asn Glu Leu Lys Glu Leu Glu Gln 865 870 875 880 Lys His Ser Gln Leu Thr Glu Glu Lys Asn Leu Leu Gln Glu Gln Leu 885 890 895 Gln Ala Glu Thr Glu Leu Tyr Ala Glu Ala Glu Glu Met Arg Val Arg 900 905 910 Leu Ala Ala Lys Lys Gln Glu Leu Glu Glu Ile Leu His Glu Met Glu 915 920 925 Ala Arg Leu Glu Glu Glu Glu Asp Arg Gly Gln Gln Leu Gln Ala Glu 930 935 940 Arg Lys Lys Met Ala Gln Gln Met Leu Asp Leu Glu Glu Gln Leu Glu 945 950 955 960 Glu Glu Glu Ala Ala Arg Gln Lys Leu Gln Leu Glu Lys Val Thr Ala 965 970 975 Glu Ala Lys Ile Lys Lys Leu Glu Asp Glu Ile Leu Val Met Asp Asp 980 985 990 Gln Asn Asn Lys Leu Ser Lys Glu Arg Lys Leu Leu Glu Glu Arg Ile 995 1000 1005 Ser Asp Leu Thr Thr Asn Leu Ala Glu Glu Glu Glu Lys Ala Lys Asn 1010 1015 1020 Leu Thr Lys Leu Lys Asn Lys His Glu Ser Met Ile Ser Glu Leu Glu 1025 1030 1035 1040 Val Arg Leu Lys Lys Glu Glu Lys Ser Arg Gln Glu Leu Glu Lys Leu 1045 1050 1055 Lys Arg Lys Leu Glu Gly Asp Ala Ser Asp Phe His Glu Gln Ile Ala 1060 1065 1070 Asp Leu Gln Ala Gln Ile Ala Glu Leu Lys Met Gln Leu Ala Lys Lys 1075 1080 1085 Glu Glu Glu Leu Gln Ala Ala Leu Ala Arg Leu Asp Asp Glu Ile Ala 1090 1095 1100 Gln Lys Asn Asn Ala Leu Lys Lys Ile Arg Glu Leu Glu Gly His Ile 1105 1110 1115 1120 Ser Asp Leu Gln Glu Asp Leu Asp Ser Glu Arg Ala Ala Arg Asn Lys 1125 1130 1135 Ala Glu Lys Gln Lys Arg Asp Leu Gly Glu Glu Leu Glu Ala Leu Lys 1140 1145 1150 Thr Glu Leu Glu Asp Thr Leu Asp Ser Thr Ala Thr Gln Gln Glu Leu 1155 1160 1165 Arg Ala Lys Arg Glu Gln Glu Val Thr Val Leu Lys Lys Ala Leu Asp 1170 1175 1180 Glu Glu Thr Arg Ser His Glu Ala Gln Val Gln Glu Met Arg Gln Lys 1185 1190 1195 1200 His Ala Gln Ala Val Glu Glu Leu Thr Glu Gln Leu Glu Gln Phe Lys 1205 1210 1215 Arg Ala Lys Ala Asn Leu Asp Lys Asn Lys Gln Thr Leu Glu Lys Glu 1220 1225 1230 Asn Ala Asp Leu Ala Gly Glu Leu Arg Val Leu Gly Gln Ala Lys Gln 1235 1240 1245 Glu Val Glu His Lys Lys Lys Lys Leu Glu Ala Gln Val Gln Glu Leu 1250 1255 1260 Gln Ser Lys Cys Ser Asp Gly Glu Arg Ala Arg Ala Glu Leu Asn Asp 1265 1270 1275 1280 Lys Val His Lys Leu Gln Asn Glu Val Glu Ser Val Thr Gly Met Leu 1285 1290 1295 Asn Glu Ala Glu Gly Lys Ala Ile Lys Leu Ala Lys Asp Val Ala Ser 1300 1305 1310 Leu Ser Ser Gln Leu Gln Asp Thr Gln Glu Leu Leu Gln Glu Glu Thr 1315 1320 1325 Arg Gln Lys Leu Asn Val Ser Thr Lys Leu Arg Gln Leu Glu Glu Glu 1330 1335 1340 Arg Asn Ser Leu Gln Asp Gln Leu Asp Glu Glu Met Glu Ala Lys Gln 1345 1350 1355 1360 Asn Leu Glu Arg His Ile Ser Thr Leu Asn Ile Gln Leu Ser Asp Ser 1365 1370 1375 Lys Lys Lys Leu Gln Asp Phe Ala Ser Thr Val Glu Ala Leu Glu Glu 1380 1385 1390 Gly Lys Lys Arg Phe Gln Lys Glu Ile Glu Asn Leu Thr Gln Gln Tyr 1395 1400 1405 Glu Glu Lys Ala Ala Ala Tyr Asp Lys Leu Glu Lys Thr Lys Asn Arg 1410 1415 1420 Leu Gln Gln Glu Leu Asp Asp Leu Val Val Asp Leu Asp Asn Gln Arg 1425 1430 1435 1440 Gln Leu Val Ser Asn Leu Glu Lys Lys Gln Arg Lys Phe Asp Gln Leu 1445 1450 1455 Leu Ala Glu Glu Lys Asn Ile Ser Ser Lys Tyr Ala Asp Glu Arg Asp 1460 1465 1470 Arg Ala Glu Ala Glu Ala Arg Glu Lys Glu Thr Lys Ala Leu Ser Leu 1475 1480 1485 Ala Arg Ala Leu Glu Glu Ala Leu Glu Ala Lys Glu Glu Leu Glu Arg 1490 1495 1500 Thr Asn Lys Met Leu Lys Ala Glu Met Glu Asp Leu Val Ser Ser Lys 1505 1510 1515 1520 Asp Asp Val Gly Lys Asn Val His Glu Leu Glu Lys Ser Lys Arg Ala 1525 1530 1535 Leu Glu Thr Gln Met Glu Glu Met Lys Thr Gln Leu Glu Glu Leu Glu 1540 1545 1550 Asp Glu Leu Gln Ala Thr Glu Asp Ala Lys Leu Arg Leu Glu Val Asn 1555 1560 1565 Met Gln Ala Leu Lys Gly Gln Phe Glu Arg Asp Leu Gln Ala Arg Asp 1570 1575 1580 Glu Gln Asn Glu Glu Lys Arg Arg Gln Leu Gln Arg Gln Leu His Glu 1585 1590 1595 1600 Tyr Glu Thr Glu Leu Glu Asp Glu Arg Lys Gln Arg Ala Leu Ala Ala 1605 1610 1615 Ala Ala Lys Lys Lys Leu Glu Gly Asp Leu Lys Asp Leu Glu Leu Gln 1620 1625 1630 Ala Asp Ser Ala Ile Lys Gly Arg Glu Glu Ala Ile Lys Gln Leu Arg 1635 1640 1645 Lys Leu Gln Ala Gln Met Lys Asp Phe Gln Arg Glu Leu Glu Asp Ala 1650 1655 1660 Arg Ala Ser Arg Asp Glu Ile Phe Ala Thr Ala Lys Glu Asn Glu Lys 1665 1670 1675 1680 Lys Ala Lys Ser Leu Glu Ala Asp Leu Met Gln Leu Gln Glu Asp Leu 1685 1690 1695 Ala Ala Ala Glu Arg Ala Arg Lys Gln Ala Asp Leu Glu Lys Glu Glu 1700 1705 1710 Leu Ala Glu Glu Leu Ala Ser Ser Leu Ser Gly Arg Asn Ala Leu Gln 1715 1720 1725 Asp Glu Lys Arg Arg Leu Glu Ala Arg Ile Ala Gln Leu Glu Glu Glu 1730 1735 1740 Leu Glu Glu Glu Gln Gly Asn Met Glu Ala Met Ser Asp Arg Val Arg 1745 1750 1755 1760 Lys Ala Thr Gln Gln Ala Glu Gln Leu Ser Asn Glu Leu Ala Thr Glu 1765 1770 1775 Arg Ser Thr Ala Gln Lys Asn Glu Ser Ala Arg Gln Gln Leu Glu Arg 1780 1785 1790 Gln Asn Lys Glu Leu Arg Ser Lys Leu His Glu Met Glu Gly Ala Val 1795 1800 1805 Lys Ser Lys Phe Lys Ser Thr Ile Ala Ala Leu Glu Ala Lys Ile Ala 1810 1815 1820 Gln Leu Glu Glu Gln Val Glu Gln Glu Ala Arg Glu Lys Gln Ala Ala 1825 1830 1835 1840 Thr Lys Ser Leu Lys Gln Lys Asp Lys Lys Leu Lys Glu Ile Leu Leu 1845 1850 1855 Gln Val Glu Asp Glu Arg Lys Met Ala Glu Gln Tyr Lys Glu Gln Ala 1860 1865 1870 Glu Lys Gly Asn Ala Arg Val Lys Gln Leu Lys Arg Gln Leu Glu Glu 1875 1880 1885 Ala Glu Glu Glu Ser Gln Arg Ile Asn Ala Asn Arg Arg Lys Leu Gln 1890 1895 1900 Arg Glu Leu Asp Glu Ala Thr Glu Ser Asn Glu Ala Met Gly Arg Glu 1905 1910 1915 1920 Val Asn Ala Leu Lys Ser Lys Leu Arg Arg Gly Asn Glu Thr Ser Phe 1925 1930 1935 Val Pro Ser Arg Arg Ser Gly Gly Arg Arg Val Ile Glu Asn Ala Asp 1940 1945 1950 Gly Ser Glu Glu Glu Thr Asp Thr Arg Asp Ala Asp Phe Asn Gly Thr 1955 1960 1965 Lys Ala Ser Glu 1970 <210> 12 <211> 434 <212> PRT <213> Homo sapiens <400> 12 Met Ser Ala Asp Gly Ala Glu Ala Asp Gly Ser Thr Gln Val Thr Val 1 5 10 15 Glu Glu Pro Val Gln Gln Pro Ser Val Val Asp Arg Val Ala Ser Met 20 25 30 Pro Leu Ile Ser Ser Thr Cys Asp Met Val Ser Ala Ala Tyr Ala Ser 35 40 45 Thr Lys Glu Ser Tyr Pro His Ile Lys Thr Val Cys Asp Ala Ala Glu 50 55 60 Lys Gly Val Arg Thr Leu Thr Ala Ala Ala Val Ser Gly Ala Gln Pro 65 70 75 80 Ile Leu Ser Lys Leu Glu Pro Gln Ile Ala Ser Ala Ser Glu Tyr Ala 85 90 95 His Arg Gly Leu Asp Lys Leu Glu Glu Asn Leu Pro Ile Leu Gln Gln 100 105 110 Pro Thr Glu Lys Val Leu Ala Asp Thr Lys Glu Leu Val Ser Ser Lys 115 120 125 Val Ser Gly Ala Gln Glu Met Val Ser Ser Ala Lys Asp Thr Val Ala 130 135 140 Thr Gln Leu Ser Glu Ala Val Asp Ala Thr Arg Gly Ala Val Gln Ser 145 150 155 160 Gly Val Asp Lys Thr Lys Ser Val Val Thr Gly Gly Val Gln Ser Val 165 170 175 Met Gly Ser Arg Leu Gly Gln Met Val Leu Ser Gly Val Asp Thr Val 180 185 190 Leu Gly Lys Ser Glu Glu Trp Ala Asp Asn His Leu Pro Leu Thr Asp 195 200 205 Ala Glu Leu Ala Arg Ile Ala Thr Ser Leu Asp Gly Phe Asp Val Ala 210 215 220 Ser Val Gln Gln Gln Arg Gln Glu Gln Ser Tyr Phe Val Arg Leu Gly 225 230 235 240 Ser Leu Ser Glu Arg Leu Arg Gln His Ala Tyr Glu His Ser Leu Gly 245 250 255 Lys Leu Arg Ala Thr Lys Gln Arg Ala Gln Glu Ala Leu Leu Gln Leu 260 265 270 Ser Gln Val Leu Ser Leu Met Glu Thr Val Lys Gln Gly Val Asp Gln 275 280 285 Lys Leu Val Glu Gly Gln Glu Lys Leu His Gln Met Trp Leu Ser Trp 290 295 300 Asn Gln Lys Gln Leu Gln Gly Pro Glu Lys Glu Pro Pro Lys Pro Glu 305 310 315 320 Gln Val Glu Ser Arg Ala Leu Thr Met Phe Arg Asp Ile Ala Gln Gln 325 330 335 Leu Gln Ala Thr Cys Thr Ser Leu Gly Ser Ser Ile Gln Gly Leu Pro 340 345 350 Thr Asn Val Lys Asp Gln Val Gln Gln Ala Arg Arg Gln Val Glu Asp 355 360 365 Leu Gln Ala Thr Phe Ser Ser Ile His Ser Phe Gln Asp Leu Ser Ser 370 375 380 Ser Ile Leu Ala Gln Ser Arg Glu Arg Val Ala Ser Ala Arg Glu Ala 385 390 395 400 Leu Asp His Met Val Glu Tyr Val Ala Gln Asn Thr Pro Val Thr Trp 405 410 415 Leu Val Gly Pro Phe Ala Pro Gly Ile Thr Glu Lys Ala Pro Glu Glu 420 425 430 Lys Lys <210> 13 <211> 51 <212> PRT <213> Homo sapiens <400> 13 Ala Gly Thr Ala Thr Cys Ala Thr Cys Ala Cys Thr Thr Cys Thr Cys 1 5 10 15 Cys Ala Cys Ala Ala Thr Gly Thr Gly Thr Thr Cys Thr Thr Ala Ala 20 25 30 Gly Gly Gly Cys Ala Gly Ala Ala Thr Thr Cys Cys Ala Gly Ala Ala 35 40 45 Cys Thr Thr 50 <210> 14 <211> 473 <212> PRT <213> Homo sapiens <400> 14 Met Gly Ala Val Leu Gly Val Phe Ser Leu Ala Ser Trp Val Pro Cys 1 5 10 15 Leu Cys Ser Gly Ala Ser Cys Leu Leu Cys Ser Cys Cys Pro Asn Ser 20 25 30 Lys Asn Ser Thr Val Thr Arg Leu Ile Tyr Ala Phe Ile Leu Leu Leu 35 40 45 Ser Thr Val Val Ser Tyr Ile Met Gln Arg Lys Glu Met Glu Thr Tyr 50 55 60 Leu Lys Lys Ile Pro Gly Phe Cys Glu Gly Gly Phe Lys Ile His Glu 65 70 75 80 Ala Asp Ile Asn Ala Asp Lys Asp Cys Asp Val Leu Val Gly Tyr Lys 85 90 95 Ala Val Tyr Arg Ile Ser Phe Ala Met Ala Ile Phe Phe Phe Val Phe 100 105 110 Ser Leu Leu Met Phe Lys Val Lys Thr Ser Lys Asp Leu Arg Ala Ala 115 120 125 Val His Asn Gly Phe Trp Phe Phe Lys Ile Ala Ala Leu Ile Gly Ile 130 135 140 Met Val Gly Ser Phe Tyr Ile Pro Gly Gly Tyr Phe Ser Ser Val Trp 145 150 155 160 Phe Val Val Gly Met Ile Gly Ala Ala Leu Phe Ile Leu Ile Gln Leu 165 170 175 Val Leu Leu Val Asp Phe Ala His Ser Trp Asn Glu Ser Trp Val Asn 180 185 190 Arg Met Glu Glu Gly Asn Pro Arg Leu Trp Tyr Ala Ala Leu Leu Ser 195 200 205 Phe Thr Ser Ala Phe Tyr Ile Leu Ser Ile Ile Cys Val Gly Leu Leu 210 215 220 Tyr Thr Tyr Tyr Thr Lys Pro Asp Gly Cys Thr Glu Asn Lys Phe Phe 225 230 235 240 Ile Ser Ile Asn Leu Ile Leu Cys Val Val Ala Ser Ile Ile Ser Ile 245 250 255 His Pro Lys Ile Gln Glu His Gln Pro Arg Ser Gly Leu Leu Gln Ser 260 265 270 Ser Leu Ile Thr Leu Tyr Thr Met Tyr Leu Thr Trp Ser Ala Met Ser 275 280 285 Asn Glu Pro Asp Arg Ser Cys Asn Pro Asn Leu Met Ser Phe Ile Thr 290 295 300 Arg Ile Thr Ala Pro Thr Leu Ala Pro Gly Asn Ser Thr Ala Val Val 305 310 315 320 Pro Thr Pro Thr Pro Pro Ser Lys Ser Gly Ser Leu Leu Asp Ser Asp 325 330 335 Asn Phe Ile Gly Leu Phe Val Phe Val Leu Cys Leu Leu Tyr Ser Ser 340 345 350 Ile Arg Thr Ser Thr Asn Ser Gln Val Asp Lys Leu Thr Leu Ser Gly 355 360 365 Ser Asp Ser Val Ile Leu Gly Asp Thr Thr Thr Ser Gly Ala Ser Asp 370 375 380 Glu Glu Asp Gly Gln Pro Arg Arg Ala Val Asp Asn Glu Lys Glu Gly 385 390 395 400 Val Gln Tyr Ser Tyr Ser Leu Phe His Leu Met Leu Cys Leu Ala Ser 405 410 415 Leu Tyr Ile Met Met Thr Leu Thr Ser Trp Tyr Ser Pro Asp Ala Lys 420 425 430 Phe Gln Ser Met Thr Ser Lys Trp Pro Ala Val Trp Val Lys Ile Ser 435 440 445 Ser Ser Trp Val Cys Leu Leu Leu Tyr Val Trp Thr Leu Val Ala Pro 450 455 460 Leu Val Leu Thr Ser Arg Asp Phe Ser 465 470 <210> 15 <211> 435 <212> PRT <213> Homo sapiens <400> 15 Met Glu Gly Gln Thr Pro Gly Ser Arg Gly Leu Pro Glu Lys Pro His 1 5 10 15 Pro Ala Thr Ala Ala Ala Thr Leu Ser Ser Met Gly Ala Val Phe Ile 20 25 30 Leu Met Lys Ser Ala Leu Gly Ala Gly Leu Leu Asn Phe Pro Trp Ala 35 40 45 Phe Ser Lys Ala Gly Gly Val Val Pro Ala Phe Leu Val Glu Leu Val 50 55 60 Ser Leu Val Phe Leu Ile Ser Gly Leu Val Ile Leu Gly Tyr Ala Ala 65 70 75 80 Ala Val Ser Gly Gln Ala Thr Tyr Gln Gly Val Val Arg Gly Leu Cys 85 90 95 Gly Pro Ala Ile Gly Lys Leu Cys Glu Ala Cys Phe Leu Leu Asn Leu 100 105 110 Leu Met Ile Ser Val Ala Phe Leu Arg Val Ile Gly Asp Gln Leu Glu 115 120 125 Lys Leu Cys Asp Ser Leu Leu Ser Gly Thr Pro Pro Ala Pro Gln Pro 130 135 140 Trp Tyr Ala Asp Gln Arg Phe Thr Leu Pro Leu Leu Ser Val Leu Val 145 150 155 160 Ile Leu Pro Leu Ser Ala Pro Arg Glu Ile Ala Phe Gln Lys Tyr Thr 165 170 175 Ser Ile Leu Gly Thr Leu Ala Ala Cys Tyr Leu Ala Leu Val Ile Thr 180 185 190 Val Gln Tyr Tyr Leu Trp Pro Gln Gly Leu Val Arg Glu Ser His Pro 195 200 205 Ser Leu Ser Pro Ala Ser Trp Thr Ser Val Phe Ser Val Phe Pro Thr 210 215 220 Ile Cys Phe Gly Phe Gln Cys His Glu Ala Ala Val Ser Ile Tyr Cys 225 230 235 240 Ser Met Arg Lys Arg Ser Leu Ser His Trp Ala Leu Val Ser Val Leu 245 250 255 Ser Leu Leu Ala Cys Cys Leu Ile Tyr Ser Leu Thr Gly Val Tyr Gly 260 265 270 Phe Leu Thr Phe Gly Thr Glu Val Ser Ala Asp Val Leu Met Ser Tyr 275 280 285 Pro Gly Asn Asp Met Val Ile Ile Val Ala Arg Val Leu Phe Ala Val 290 295 300 Ser Ile Val Thr Val Tyr Pro Ile Val Leu Phe Leu Gly Arg Ser Val 305 310 315 320 Met Gln Asp Phe Trp Arg Arg Ser Cys Leu Gly Gly Trp Gly Pro Ser 325 330 335 Ala Leu Ala Asp Pro Ser Gly Leu Trp Val Arg Met Pro Leu Thr Ile 340 345 350 Leu Trp Val Thr Val Thr Leu Ala Met Ala Leu Phe Met Pro Asp Leu 355 360 365 Ser Glu Ile Val Ser Ile Ile Gly Gly Ile Ser Ser Phe Phe Ile Phe 370 375 380 Ile Phe Pro Gly Leu Cys Leu Ile Cys Ala Met Gly Val Glu Pro Ile 385 390 395 400 Gly Pro Arg Val Lys Cys Cys Leu Glu Val Trp Gly Val Val Ser Val 405 410 415 Leu Val Gly Thr Phe Ile Phe Gly Gln Ser Thr Ala Ala Ala Val Trp 420 425 430 Glu Met Phe 435 <210> 16 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 16 gagtattttc tgcctcattt ctcagtttga ctgcctacca accatatttg 50 <210> 17 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 17 gagtattttc tgcctcattt ctcagtttga ctgcctacca accatatttg 50 <210> 18 <211> 51 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 18 agtatcatca cttctccaca atgtgttctt aagggcagaa ttccagaact t 51 <210> 19 <211> 47 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 19 tcgtgacatt ggagaccttg ctctgttctt ggaaatcctg ctcatgg 47 <210> 20 <211> 48 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 20 ggaagcaagt gtttcaactg ttccggaatg tttgttgtat gccttcat 48 <210> 21 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 21 ggtgggatcc tcttttcaca caagcagaag atcattaatt gggtcctgat 50 <210> 22 <211> 48 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 22 tctcagggag gctttcctct ggtgaacagg gaattgattc aagattgg 48 <210> 23 <211> 44 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 23 cgttgctggt tgaaatcccg tccaactaac aaatgccaaa ggga 44 <210> 24 <211> 46 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 24 cagataatcc agcaggagtg caaccaggca ctcactctta tgaatt 46 <210> 25 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 25 ccccacagtg agataataat gaccaactca ggaaaacagg aaaggaggtt 50 <210> 26 <211> 44 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 26 ctgctgagcg gcccagtaac tcaatggatt gtgcagacac tgag 44 <210> 27 <211> 46 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 27 agcatttcaa caaggcttac cactcccctg cagaattttt tttcct 46 <210> 28 <211> 43 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 28 gtattctggg aacgtcggag actggtaagt gtgggaacaa ggc 43 <210> 29 <211> 52 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 29 cctgtctctt atattcttat ggcccaatgc atttgatctg tgcagattga ta 52 <210> 30 <211> 49 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 30 aaggaggcag aaggcatcag tctggtactt tgcttcccat tgtcttgga 49 <110> CHO, Han-Jun <120> Gene mutations biomarker that predicts recurrence for prostate cancer <130> P-20200303 <160> 30 <170> KoPatentIn 3.0 <210> 1 <211> 514 <212> PRT <213> Homo sapiens <400> 1 Met Thr Leu Ile Trp Arg His Leu Leu Arg Pro Leu Cys Leu Val Thr 1 5 10 15 Ser Ala Pro Arg Ile Leu Glu Met His Pro Phe Leu Ser Leu Gly Thr 20 25 30 Ser Arg Thr Ser Val Thr Lys Leu Ser Leu His Thr Lys Pro Arg Met 35 40 45 Pro Pro Cys Asp Phe Met Pro Glu Arg Tyr Gln Ser Leu Gly Tyr Asn 50 55 60 Arg Val Leu Glu Ile His Lys Glu His Leu Ser Pro Val Val Thr Ala 65 70 75 80 Tyr Phe Gln Lys Pro Leu Leu Leu His Gln Gly His Met Glu Trp Leu 85 90 95 Phe Asp Ala Glu Gly Ser Arg Tyr Leu Asp Phe Phe Ser Gly Ile Val 100 105 110 Thr Val Ser Val Gly His Cys His Pro Lys Val Asn Ala Val Ala Gln 115 120 125 Lys Gln Leu Gly Arg Leu Trp His Thr Ser Thr Val Phe Phe His Pro 130 135 140 Pro Met His Glu Tyr Ala Glu Lys Leu Ala Ala Leu Leu Pro Glu Pro 145 150 155 160 Leu Lys Val Ile Phe Leu Val Asn Ser Gly Ser Glu Ala Asn Glu Leu 165 170 175 Ala Met Leu Met Ala Arg Ala His Ser Asn Asn Ile Asp Ile Ile Ser 180 185 190 Phe Arg Gly Ala Tyr His Gly Cys Ser Pro Tyr Thr Leu Gly Leu Thr 195 200 205 Asn Val Gly Thr Tyr Lys Met Glu Leu Pro Gly Gly Thr Gly Cys Gln 210 215 220 Pro Thr Met Cys Pro Asp Val Phe Arg Gly Pro Trp Gly Gly Ser His 225 230 235 240 Cys Arg Asp Ser Pro Val Gln Thr Ile Arg Lys Cys Ser Cys Ala Pro 245 250 255 Asp Cys Cys Gln Ala Lys Asp Gln Tyr Ile Glu Gln Phe Lys Asp Thr 260 265 270 Leu Ser Thr Ser Val Ala Lys Ser Ile Ala Gly Phe Phe Ala Glu Pro 275 280 285 Ile Gln Gly Val Asn Gly Val Val Gln Tyr Pro Lys Gly Phe Leu Lys 290 295 300 Glu Ala Phe Glu Leu Val Arg Ala Arg Gly Gly Val Cys Ile Ala Asp 305 310 315 320 Glu Val Gln Thr Gly Phe Gly Arg Leu Gly Ser His Phe Trp Gly Phe 325 330 335 Gln Thr His Asp Val Leu Pro Asp Ile Val Thr Met Ala Lys Gly Ile 340 345 350 Gly Asn Gly Phe Pro Met Ala Ala Val Ile Thr Thr Pro Glu Ile Ala 355 360 365 Lys Ser Leu Ala Lys Cys Leu Gln His Phe Asn Thr Phe Gly Gly Asn 370 375 380 Pro Met Ala Cys Ala Ile Gly Ser Ala Val Leu Glu Val Ile Lys Glu 385 390 395 400 Glu Asn Leu Gln Glu Asn Ser Gln Glu Val Gly Thr Tyr Met Leu Leu 405 410 415 Lys Phe Ala Lys Leu Arg Asp Glu Phe Glu Ile Val Gly Asp Val Arg 420 425 430 Gly Lys Gly Leu Met Ile Gly Ile Glu Met Val Gln Asp Lys Ile Ser 435 440 445 Cys Arg Pro Leu Pro Arg Glu Glu Val Asn Gln Ile His Glu Asp Cys 450 455 460 Lys His Met Gly Leu Leu Val Gly Arg Gly Ser Ile Phe Ser Gln Thr 465 470 475 480 Phe Arg Ile Ala Pro Ser Met Cys Ile Thr Lys Pro Glu Val Asp Phe 485 490 495 Ala Val Glu Val Phe Arg Ser Ala Leu Thr Gln His Met Glu Arg Arg 500 505 510 Ala Lys <210> 2 <211> 1938 <212> PRT <213> Homo sapiens <400> 2 Met Ser Arg Trp Leu Trp Pro Trp Ser Asn Cys Val Lys Glu Arg Val 1 5 10 15 Cys Arg Tyr Leu Leu His His Tyr Leu Gly His Phe Phe Gln Glu His 20 25 30 Leu Ser Leu Asp Gln Leu Ser Leu Asp Leu Tyr Lys Gly Ser Val Ala 35 40 45 Leu Arg Asp Ile His Leu Glu Ile Trp Ser Val Asn Glu Val Leu Glu 50 55 60 Ser Met Glu Ser Pro Leu Glu Leu Val Glu Gly Phe Val Gly Ser Ile 65 70 75 80 Glu Val Ala Val Pro Trp Ala Ala Leu Leu Thr Asp His Cys Thr Val 85 90 95 Arg Val Ser Gly Leu Gln Leu Thr Leu Gln Pro Arg Arg Gly Pro Ala 100 105 110 Pro Gly Ala Ala Asp Ser Gln Ser Trp Ala Ser Cys Met Thr Thr Ser 115 120 125 Leu Gln Leu Ala Gln Glu Cys Leu Arg Asp Gly Leu Pro Glu Pro Ser 130 135 140 Glu Pro Pro Gln Pro Leu Glu Gly Leu Glu Met Phe Ala Gln Thr Ile 145 150 155 160 Glu Thr Val Leu Arg Arg Ile Lys Val Thr Phe Leu Asp Thr Val Val 165 170 175 Arg Val Glu His Ser Pro Gly Asp Gly Glu Arg Val Gly Val Ala Val Glu 180 185 190 Val Arg Val Gln Arg Leu Glu Tyr Cys Asp Glu Ala Val Arg Asp Pro 195 200 205 Ser Gln Ala Pro Pro Val Asp Val His Gln Pro Pro Ala Phe Leu His 210 215 220 Lys Leu Leu Gln Leu Ala Gly Val Arg Leu His Tyr Glu Glu Leu Pro 225 230 235 240 Ala Gln Glu Glu Pro Pro Glu Pro Pro Leu Gln Ile Gly Ser Cys Ser 245 250 255 Gly Tyr Met Glu Leu Met Val Lys Leu Lys Gln Asn Glu Ala Phe Pro 260 265 270 Gly Pro Lys Leu Glu Val Ala Gly Gln Leu Gly Ser Leu His Leu Leu 275 280 285 Leu Thr Pro Arg Gln Leu Gln Gln Leu Gln Glu Leu Leu Ser Ala Val 290 295 300 Ser Leu Thr Asp His Glu Gly Leu Ala Asp Lys Leu Asn Lys Ser Arg 305 310 315 320 Pro Leu Gly Ala Glu Asp Leu Trp Leu Ile Glu Gln Asp Leu Asn Gln 325 330 335 Gln Leu Gln Ala Gly Ala Val Ala Glu Pro Leu Ser Pro Asp Pro Leu 340 345 350 Thr Asn Pro Leu Leu Asn Leu Asp Asn Thr Asp Leu Phe Phe Ser Met 355 360 365 Ala Gly Leu Thr Ser Ser Val Ala Ser Ala Leu Ser Glu Leu Ser Leu 370 375 380 Ser Asp Val Asp Leu Ala Ser Ser Val Arg Ser Asp Met Ala Ser Arg 385 390 395 400 Arg Leu Ser Ala Gln Ala His Pro Ala Gly Lys Met Ala Pro Asn Pro 405 410 415 Leu Leu Asp Thr Met Arg Pro Asp Ser Leu Leu Lys Met Thr Leu Gly 420 425 430 Gly Val Thr Leu Thr Leu Leu Gln Thr Ser Ala Pro Ser Ser Gly Pro 435 440 445 Pro Asp Leu Ala Thr His Phe Phe Thr Glu Phe Asp Ala Thr Lys Asp 450 455 460 Gly Pro Phe Gly Ser Arg Asp Phe His His Leu Arg Pro Arg Phe Gln 465 470 475 480 Arg Ala Cys Pro Cys Ser His Val Arg Leu Thr Gly Thr Ala Val Gln 485 490 495 Leu Ser Trp Glu Leu Arg Thr Gly Ser Arg Gly Arg Arg Thr Thr Ser 500 505 510 Met Glu Val His Phe Gly Gln Leu Glu Val Leu Glu Cys Leu Trp Pro 515 520 525 Arg Gly Thr Ser Glu Pro Glu Tyr Thr Glu Ile Leu Thr Phe Pro Gly 530 535 540 Thr Leu Gly Ser Gln Ala Ser Ala Arg Pro Cys Ala His Leu Arg His 545 550 555 560 Thr Gln Ile Leu Arg Arg Val Pro Lys Ser Arg Pro Arg Arg Ser Val 565 570 575 Ala Cys His Cys His Ser Glu Leu Ala Leu Asp Leu Ala Asn Phe Gln 580 585 590 Ala Asp Val Glu Leu Gly Ala Leu Asp Arg Leu Ala Ala Leu Leu Arg 595 600 605 Leu Ala Thr Val Pro Ala Glu Pro Pro Ala Gly Leu Leu Thr Glu Pro 610 615 620 Leu Pro Ala Met Glu Gln Gln Thr Val Phe Arg Leu Ser Ala Pro Arg 625 630 635 640 Ala Thr Leu Arg Leu Arg Phe Pro Ile Ala Asp Leu Arg Pro Glu Pro 645 650 655 Asp Pro Trp Ala Gly Gln Ala Val Arg Ala Glu Gln Leu Arg Leu Glu 660 665 670 Leu Ser Glu Pro Gln Phe Arg Ser Glu Leu Ser Ser Gly Pro Gly Pro 675 680 685 Pro Val Pro Thr His Leu Glu Leu Thr Cys Ser Asp Leu His Gly Ile 690 695 700 Tyr Glu Asp Gly Gly Lys Pro Pro Val Pro Cys Leu Arg Val Ser Lys 705 710 715 720 Ala Leu Asp Pro Lys Ser Thr Gly Arg Lys Tyr Phe Leu Pro Gln Val 725 730 735 Val Val Thr Val Asn Pro Gln Ser Ser Ser Thr Gln Trp Glu Val Ala 740 745 750 Pro Glu Lys Gly Glu Glu Leu Glu Leu Ser Val Glu Ser Pro Cys Glu 755 760 765 Leu Arg Glu Pro Glu Pro Ser Pro Phe Ser Ser Lys Arg Thr Met Tyr 770 775 780 Glu Thr Glu Glu Met Val Ile Pro Gly Asp Pro Glu Glu Met Arg Thr 785 790 795 800 Phe Gln Ser Arg Thr Leu Ala Leu Ser Arg Cys Ser Leu Glu Val Ile 805 810 815 Leu Pro Ser Val His Ile Phe Leu Pro Ser Lys Glu Val Tyr Glu Ser 820 825 830 Ile Tyr Asn Arg Ile Asn Asn Asp Leu Leu Met Trp Glu Pro Ala Asp 835 840 845 Leu Leu Pro Thr Pro Asp Pro Ala Ala Gln Pro Ser Gly Phe Pro Gly 850 855 860 Pro Ser Gly Phe Trp His Asp Ser Phe Lys Met Cys Lys Ser Ala Phe 865 870 875 880 Lys Leu Ala Asn Cys Phe Asp Leu Thr Pro Asp Ser Asp Ser Asp Asp 885 890 895 Glu Asp Ala His Phe Phe Ser Val Gly Ala Ser Gly Gly Pro Gln Ala 900 905 910 Ala Ala Pro Glu Ala Pro Ser Leu His Leu Gln Ser Thr Phe Ser Thr 915 920 925 Leu Val Thr Val Leu Lys Gly Arg Ile Thr Ala Leu Cys Glu Thr Lys 930 935 940 Asp Glu Gly Gly Lys Arg Leu Glu Ala Val His Gly Glu Leu Val Leu 945 950 955 960 Asp Met Glu His Gly Thr Leu Phe Ser Val Ser Gln Tyr Cys Gly Gln 965 970 975 Pro Gly Leu Gly Tyr Phe Cys Leu Glu Ala Glu Lys Ala Thr Leu Tyr 980 985 990 His Arg Ala Ala Val Asp Asp Tyr Pro Leu Pro Ser His Leu Asp Leu 995 1000 1005 Pro Ser Phe Ala Pro Pro Ala Gln Leu Ala Pro Thr Ile Tyr Pro Ser 1010 1015 1020 Glu Glu Gly Val Thr Glu Arg Gly Ala Ser Gly Arg Lys Gly Gln Gly 1025 1030 1035 1040 Arg Gly Pro His Met Leu Ser Thr Ala Val Arg Ile His Leu Asp Pro 1045 1050 1055 His Lys Asn Val Lys Glu Phe Leu Val Thr Leu Arg Leu His Lys Ala 1060 1065 1070 Thr Leu Arg His Tyr Met Ala Leu Pro Glu Gln Ser Trp His Ser Gln 1075 1080 1085 Leu Leu Glu Phe Leu Asp Val Leu Asp Asp Pro Val Leu Gly Tyr Leu 1090 1095 1100 Pro Pro Thr Val Ile Thr Ile Leu His Thr His Leu Phe Ser Cys Ser 1105 1110 1115 1120 Val Asp Tyr Arg Pro Leu Tyr Leu Pro Val Arg Val Leu Ile Thr Ala 1125 1130 1135 Glu Thr Phe Thr Leu Ser Ser Asn Ile Ile Met Asp Thr Ser Thr Phe 1140 1145 1150 Leu Leu Arg Phe Ile Leu Asp Asp Ser Ala Leu Tyr Leu Ser Asp Lys 1155 1160 1165 Cys Glu Val Glu Thr Leu Asp Leu Arg Arg Asp Tyr Val Cys Val Leu 1170 1175 1180 Asp Val Asp Leu Leu Glu Leu Val Ile Lys Thr Trp Lys Gly Ser Thr 1185 1190 1195 1200 Glu Gly Lys Leu Ser Gln Pro Leu Phe Glu Leu Arg Cys Ser Asn Asn 1205 1210 1215 Val Val His Val His Ser Cys Ala Asp Ser Cys Ala Leu Leu Val Asn 1220 1225 1230 Leu Leu Gln Tyr Val Met Ser Thr Gly Asp Leu His Pro Pro Pro Arg 1235 1240 1245 Pro Pro Ser Pro Thr Glu Ile Ala Gly Gln Lys Leu Ser Glu Ser Pro 1250 1255 1260 Ala Ser Leu Pro Ser Cys Pro Pro Val Glu Thr Ala Leu Ile Asn Gln 1265 1270 1275 1280 Arg Asp Leu Ala Asp Ala Leu Leu Asp Thr Glu Arg Ser Leu Arg Glu 1285 1290 1295 Leu Ala Gln Pro Ser Gly Gly His Leu Pro Gln Ala Ser Pro Ile Ser 1300 1305 1310 Val Tyr Leu Phe Pro Gly Glu Arg Ser Gly Ala Pro Pro Pro Ser Pro 1315 1320 1325 Pro Val Gly Gly Pro Ala Gly Ser Leu Gly Ser Cys Ser Glu Glu Lys 1330 1335 1340 Glu Asp Glu Arg Glu Glu Glu Gly Asp Gly Asp Thr Leu Asp Ser Asp 1345 1350 1355 1360 Glu Phe Cys Ile Leu Asp Ala Pro Gly Leu Gly Ile Pro Pro Arg Asp 1365 1370 1375 Gly Glu Pro Val Val Thr Gln Leu His Pro Gly Pro Ile Val Val Arg 1380 1385 1390 Asp Gly Tyr Phe Ser Arg Pro Ile Gly Ser Thr Asp Leu Leu Arg Ala 1395 1400 1405 Pro Ala His Phe Pro Val Pro Ser Thr Arg Val Val Leu Arg Glu Val 1410 1415 1420 Ser Leu Val Trp His Leu Tyr Gly Gly Arg Asp Phe Gly Pro His Pro 1425 1430 1435 1440 Gly His Arg Ala Arg Thr Gly Leu Ser Gly Pro Arg Ser Ser Pro Ser 1445 1450 1455 Arg Cys Ser Gly Pro Asn Arg Pro Gln Asn Ser Trp Arg Thr Gln Gly 1460 1465 1470 Gly Ser Gly Arg Gln His His Val Leu Met Glu Ile Gln Leu Ser Lys 1475 1480 1485 Val Ser Phe Gln His Glu Val Tyr Pro Ala Glu Pro Ala Thr Gly Pro 1490 1495 1500 Ala Ala Pro Ser Gln Glu Leu Glu Glu Arg Pro Leu Ser Arg Gln Val 1505 1510 1515 1520 Phe Ile Val Gln Glu Leu Glu Val Arg Asp Arg Leu Ala Ser Ser Gln 1525 1530 1535 Ile Asn Lys Phe Leu Tyr Leu His Thr Ser Glu Arg Met Pro Arg Arg 1540 1545 1550 Ala His Ser Asn Met Leu Thr Ile Lys Ala Leu His Val Ala Pro Thr 1555 1560 1565 Thr Asn Leu Gly Gly Pro Glu Cys Cys Leu Arg Val Ser Leu Met Pro 1570 1575 1580 Leu Arg Leu Asn Val Asp Gln Asp Ala Leu Phe Phe Leu Lys Asp Phe 1585 1590 1595 1600 Phe Thr Ser Leu Val Ala Gly Ile Asn Pro Val Val Pro Gly Glu Thr 1605 1610 1615 Ser Ala Glu Ala Arg Pro Glu Thr Arg Ala Gln Pro Ser Ser Pro Leu 1620 1625 1630 Glu Gly Gln Ala Glu Gly Val Glu Thr Thr Gly Ser Gln Glu Ala Pro 1635 1640 1645 Gly Gly Gly His Ser Pro Ser Pro Pro Asp Gln Gln Pro Ile Tyr Phe 1650 1655 1660 Arg Glu Phe Arg Phe Thr Ser Glu Val Pro Ile Trp Leu Asp Tyr His 1665 1670 1675 1680 Gly Lys His Val Thr Met Asp Gln Val Gly Thr Phe Ala Gly Leu Leu 1685 1690 1695 Ile Gly Leu Ala Gln Leu Asn Cys Ser Glu Leu Lys Leu Lys Arg Leu 1700 1705 1710 Cys Cys Arg His Gly Leu Leu Gly Val Asp Lys Val Leu Gly Tyr Ala 1715 1720 1725 Leu Asn Glu Trp Leu Gln Asp Ile Arg Lys Asn Gln Leu Pro Gly Leu 1730 1735 1740 Leu Gly Gly Val Gly Pro Met His Ser Val Val Gln Leu Phe Gln Gly 1745 1750 1755 1760 Phe Arg Asp Leu Leu Trp Leu Pro Ile Glu Gln Tyr Arg Lys Asp Gly 1765 1770 1775 Arg Leu Met Arg Gly Leu Gln Arg Gly Ala Ala Ser Phe Gly Ser Ser 1780 1785 1790 Thr Ala Ser Ala Ala Leu Glu Leu Ser Asn Arg Leu Val Gln Ala Ile 1795 1800 1805 Gln Ala Thr Ala Glu Thr Val Tyr Asp Ile Leu Ser Pro Ala Ala Pro 1810 1815 1820 Val Ser Arg Ser Leu Gln Asp Lys Arg Ser Ala Arg Arg Leu Arg Arg 1825 1830 1835 1840 Gly Gln Gln Pro Ala Asp Leu Arg Glu Gly Val Ala Lys Ala Tyr Asp 1845 1850 1855 Thr Val Arg Glu Gly Ile Leu Asp Thr Ala Gln Thr Ile Cys Asp Val 1860 1865 1870 Ala Ser Arg Gly His Glu Gln Lys Gly Leu Thr Gly Ala Val Gly Gly 1875 1880 1885 Val Ile Arg Gln Leu Pro Pro Thr Val Val Lys Pro Leu Ile Leu Ala 1890 1895 1900 Thr Glu Ala Thr Ser Ser Leu Leu Gly Gly Met Arg Asn Gln Ile Val 1905 1910 1915 1920 Pro Asp Ala His Lys Asp His Ala Leu Lys Trp Arg Ser Asp Ser Ala 1925 1930 1935 Gln Asp <210> 3 <211> 1218 <212> PRT <213> Homo sapiens <400> 3 Met Glu Glu Asn Ser Lys Lys Asp His Arg Ala Leu Leu Asn Gln Gly 1 5 10 15 Glu Glu Asp Glu Leu Glu Val Phe Gly Tyr Arg Asp His Asn Val Arg 20 25 30 Lys Ala Phe Cys Leu Val Ala Ser Val Leu Thr Cys Gly Gly Leu Leu 35 40 45 Leu Val Phe Tyr Trp Arg Pro Gln Trp Arg Val Trp Ala Asn Cys Ile 50 55 60 Pro Cys Pro Leu Gln Glu Ala Asp Thr Val Leu Leu Arg Thr Thr Asp 65 70 75 80 Glu Phe Gln Arg Tyr Met Arg Lys Lys Val Phe Cys Leu Tyr Leu Ser 85 90 95 Thr Leu Lys Phe Pro Val Ser Lys Lys Trp Glu Glu Ser Leu Val Ala 100 105 110 Asp Arg His Ser Val Ile Asn Gln Ala Leu Ile Lys Pro Glu Leu Lys 115 120 125 Leu Arg Cys Met Glu Val Gln Lys Ile Arg Tyr Val Trp Asn Asp Leu 130 135 140 Glu Lys Arg Phe Gln Lys Val Gly Leu Leu Glu Asp Ser Asn Ser Cys 145 150 155 160 Ser Asp Ile His Gln Thr Phe Gly Leu Gly Leu Thr Ser Glu Glu Gln 165 170 175 Glu Val Arg Arg Leu Val Cys Gly Pro Asn Ala Ile Glu Val Glu Ile 180 185 190 Gln Pro Ile Trp Lys Leu Leu Val Lys Gln Val Leu Asn Pro Phe Tyr 195 200 205 Val Phe Gln Ala Phe Thr Leu Thr Leu Trp Leu Ser Gln Gly Tyr Ile 210 215 220 Glu Tyr Ser Val Ala Ile Ile Ile Leu Thr Val Ile Ser Ile Val Leu 225 230 235 240 Ser Val Tyr Asp Leu Arg Gln Gln Ser Val Lys Leu His Asn Leu Val 245 250 255 Glu Asp His Asn Lys Val Gln Val Thr Ile Ile Val Lys Asp Lys Gly 260 265 270 Leu Glu Glu Leu Glu Ser Arg Leu Leu Val Pro Gly Asp Ile Leu Ile 275 280 285 Leu Pro Gly Lys Phe Ser Leu Pro Cys Asp Ala Val Leu Ile Asp Gly 290 295 300 Ser Cys Val Val Asn Glu Gly Met Leu Thr Gly Glu Ser Ile Pro Val 305 310 315 320 Thr Lys Thr Pro Leu Pro Gln Met Glu Asn Thr Met Pro Trp Lys Cys 325 330 335 His Ser Leu Glu Asp Tyr Arg Lys His Val Leu Phe Cys Gly Thr Glu 340 345 350 Val Ile Gln Val Lys Pro Ser Gly Gln Gly Pro Val Arg Ala Val Val 355 360 365 Leu Gln Thr Gly Tyr Asn Thr Ala Lys Gly Asp Leu Val Arg Ser Ile 370 375 380 Leu Tyr Pro Arg Pro Leu Asn Phe Lys Leu Tyr Ser Asp Ala Phe Lys 385 390 395 400 Phe Ile Val Phe Leu Ala Cys Leu Gly Val Met Gly Phe Phe Tyr Ala 405 410 415 Leu Gly Val Tyr Met Tyr His Gly Val Pro Pro Lys Asp Thr Val Thr 420 425 430 Met Ala Leu Ile Leu Leu Thr Val Thr Val Pro Pro Val Leu Pro Ala 435 440 445 Ala Leu Thr Ile Gly Asn Val Tyr Ala Gln Lys Arg Leu Lys Lys Lys 450 455 460 Lys Ile Phe Cys Ile Ser Pro Gln Arg Ile Asn Met Cys Gly Gln Ile 465 470 475 480 Asn Leu Val Cys Phe Asp Lys Thr Gly Thr Leu Thr Glu Asp Gly Leu 485 490 495 Asp Leu Trp Gly Thr Val Pro Thr Ala Asp Asn Cys Phe Gln Glu Ala 500 505 510 His Ser Phe Ala Ser Gly Gln Ala Val Pro Trp Ser Pro Leu Cys Ala 515 520 525 Ala Met Ala Ser Cys His Ser Leu Ile Leu Leu Asn Gly Thr Ile Gln 530 535 540 Gly Asp Pro Leu Asp Leu Lys Met Phe Glu Gly Thr Ala Trp Lys Met 545 550 555 560 Glu Asp Cys Ile Val Asp Ser Cys Lys Phe Gly Thr Ser Val Ser Asn 565 570 575 Ile Ile Lys Pro Gly Pro Lys Ala Ser Lys Ser Pro Val Glu Ala Ile 580 585 590 Ile Thr Leu Cys Gln Phe Pro Phe Ser Ser Ser Leu Gln Arg Met Ser 595 600 605 Val Ile Ala Gln Leu Ala Gly Glu Asn His Phe His Val Tyr Met Lys 610 615 620 Gly Ala Pro Glu Met Val Ala Arg Phe Cys Arg Ser Glu Thr Val Pro 625 630 635 640 Lys Asn Phe Pro Gln Glu Leu Arg Ser Tyr Thr Val Gln Gly Phe Arg 645 650 655 Val Ile Ala Leu Ala His Lys Thr Leu Lys Met Gly Asn Leu Ser Glu 660 665 670 Val Glu His Leu Ala Arg Glu Lys Val Glu Ser Glu Leu Thr Phe Leu 675 680 685 Gly Leu Leu Ile Met Glu Asn Arg Leu Lys Lys Glu Thr Lys Leu Val 690 695 700 Leu Lys Glu Leu Ser Glu Ala Arg Ile Arg Thr Val Met Ile Thr Gly 705 710 715 720 Asp Asn Leu Gln Thr Ala Ile Thr Val Ala Lys Asn Ser Glu Met Ile 725 730 735 Pro Pro Gly Ser Gln Val Ile Ile Val Glu Ala Asp Glu Pro Glu Glu 740 745 750 Phe Val Pro Ala Ser Val Thr Trp Gln Leu Val Glu Asn Gln Glu Thr 755 760 765 Gly Pro Gly Lys Lys Glu Ile Tyr Met His Thr Gly Asn Ser Ser Thr 770 775 780 Pro Arg Gly Glu Gly Gly Ser Cys Tyr His Phe Ala Met Ser Gly Lys 785 790 795 800 Ser Tyr Gln Val Ile Phe Gln His Phe Asn Ser Leu Leu Pro Lys Ile 805 810 815 Leu Val Asn Gly Thr Val Phe Ala Arg Met Ser Pro Gly Gln Lys Ser 820 825 830 Ser Leu Ile Glu Glu Phe Gln Lys Leu Asn Tyr Tyr Val Gly Met Cys 835 840 845 Gly Asp Gly Ala Asn Asp Cys Gly Ala Leu Lys Ala Ala His Ala Gly 850 855 860 Ile Ser Leu Ser Glu Gln Glu Ala Ser Val Ala Ser Pro Phe Thr Ser 865 870 875 880 Lys Thr Thr Asn Ile Gln Cys Val Pro His Leu Ile Arg Glu Gly Arg 885 890 895 Ala Ala Leu Val Ser Ser Phe Gly Val Phe Lys Tyr Leu Thr Met Tyr 900 905 910 Gly Ile Ile Gln Phe Ile Ser Ala Leu Leu Leu Tyr Trp Gln Leu Gln 915 920 925 Leu Phe Gly Asn Tyr Gln Tyr Leu Met Gln Asp Val Ala Ile Thr Leu 930 935 940 Met Val Cys Leu Thr Met Ser Ser Thr His Ala Tyr Pro Lys Leu Ala 945 950 955 960 Pro Tyr Arg Pro Ala Gly Gln Leu Leu Ser Pro Pro Leu Leu Leu Ser 965 970 975 Ile Phe Leu Asn Ser Cys Phe Ser Cys Ile Val Gln Ile Ser Ala Phe 980 985 990 Leu Tyr Val Lys Gln Gln Pro Trp Tyr Cys Glu Val Tyr Gln Tyr Ser 995 1000 1005 Glu Cys Phe Leu Ala Asn Gln Ser Asn Phe Ser Thr Asn Val Ser Leu 1010 1015 1020 Glu Arg Asn Trp Thr Gly Asn Ala Thr Leu Ile Pro Gly Ser Ile Leu 1025 1030 1035 1040 Ser Phe Glu Thr Thr Thr Leu Trp Pro Ile Thr Thr Ile Asn Tyr Ile 1045 1050 1055 Thr Val Ala Phe Ile Phe Ser Lys Gly Lys Pro Phe Arg Lys Pro Ile 1060 1065 1070 Tyr Thr Asn Tyr Ile Phe Ser Phe Leu Leu Leu Ala Ala Leu Gly Leu 1075 1080 1085 Thr Ile Phe Ile Leu Phe Ser Asp Phe Gln Val Ile Tyr Arg Gly Met 1090 1095 1100 Glu Leu Ile Pro Thr Ile Thr Ser Trp Arg Val Leu Ile Leu Val Val 1105 1110 1115 1120 Ala Leu Thr Gln Phe Cys Val Ala Phe Phe Val Glu Asp Ser Ile Leu 1125 1130 1135 Gln Asn His Glu Leu Trp Leu Leu Ile Lys Arg Glu Phe Gly Phe Tyr 1140 1145 1150 Ser Lys Ser Gln Tyr Arg Thr Trp Gln Lys Lys Leu Ala Glu Asp Ser 1155 1160 1165 Thr Trp Pro Pro Ile Asn Arg Thr Asp Tyr Ser Gly Asp Gly Lys Asn 1170 1175 1180 Gly Phe Tyr Ile Asn Gly Gly Tyr Glu Ser His Glu Gln Ile Pro Lys 1185 1190 1195 1200 Arg Lys Leu Lys Leu Gly Gly Gln Pro Thr Glu Gln His Phe Trp Ala 1205 1210 1215 Arg Leu <210> 4 <211> 328 <212> PRT <213> Homo sapiens <400> 4 Met Thr Val Glu Lys Glu Ala Pro Asp Ala His Phe Thr Val Asp Lys 1 5 10 15 Gln Asn Ile Ser Leu Trp Pro Arg Glu Pro Pro Pro Lys Ser Gly Pro 20 25 30 Ser Leu Val Pro Gly Lys Thr Pro Thr Val Arg Ala Ala Leu Ile Cys 35 40 45 Leu Thr Leu Val Leu Val Ala Ser Val Leu Leu Gln Ala Val Leu Tyr 50 55 60 Pro Arg Phe Met Gly Thr Ile Ser Asp Val Lys Thr Asn Val Gln Leu 65 70 75 80 Leu Lys Gly Arg Val Asp Asn Ile Ser Thr Leu Asp Ser Glu Ile Lys 85 90 95 Lys Asn Ser Asp Gly Met Glu Ala Ala Gly Val Gln Ile Gln Met Val 100 105 110 Asn Glu Ser Leu Gly Tyr Val Arg Ser Gln Phe Leu Lys Leu Lys Thr 115 120 125 Ser Val Glu Lys Ala Asn Ala Gln Ile Gln Ile Leu Thr Arg Ser Trp 130 135 140 Glu Glu Val Ser Thr Leu Asn Ala Gln Ile Pro Glu Leu Lys Ser Asp 145 150 155 160 Leu Glu Lys Ala Ser Ala Leu Asn Thr Lys Ile Arg Ala Leu Gln Gly 165 170 175 Ser Leu Glu Asn Met Ser Lys Leu Leu Lys Arg Gln Asn Asp Ile Leu 180 185 190 Gln Val Val Ser Gln Gly Trp Lys Tyr Phe Lys Gly Asn Phe Tyr Tyr 195 200 205 Phe Ser Leu Ile Pro Lys Thr Trp Tyr Ser Ala Glu Gln Phe Cys Val 210 215 220 Ser Arg Asn Ser His Leu Thr Ser Val Thr Ser Glu Ser Glu Gln Glu 225 230 235 240 Phe Leu Tyr Lys Thr Ala Gly Gly Leu Ile Tyr Trp Ile Gly Leu Thr 245 250 255 Lys Ala Gly Met Glu Gly Asp Trp Ser Trp Val Asp Asp Thr Pro Phe 260 265 270 Asn Lys Val Gln Ser Val Arg Phe Trp Ile Pro Gly Glu Pro Asn Asn 275 280 285 Ala Gly Asn Asn Glu His Cys Gly Asn Ile Lys Ala Pro Ser Leu Gln 290 295 300 Ala Trp Asn Asp Ala Pro Cys Asp Lys Thr Phe Leu Phe Ile Cys Lys 305 310 315 320 Arg Pro Tyr Val Pro Ser Glu Pro 325 <210> 5 <211> 957 <212> PRT <213> Homo sapiens <400> 5 Met Ala His Tyr Ile Thr Phe Leu Cys Met Val Leu Val Leu Leu Leu 1 5 10 15 Gln Asn Ser Val Leu Ala Glu Asp Gly Glu Val Arg Ser Ser Cys Arg 20 25 30 Thr Ala Pro Thr Asp Leu Val Phe Ile Leu Asp Gly Ser Tyr Ser Val 35 40 45 Gly Pro Glu Asn Phe Glu Ile Val Lys Lys Trp Leu Val Asn Ile Thr 50 55 60 Lys Asn Phe Asp Ile Gly Pro Lys Phe Ile Gln Val Gly Val Val Gln 65 70 75 80 Tyr Ser Asp Tyr Pro Val Leu Glu Ile Pro Leu Gly Ser Tyr Asp Ser 85 90 95 Gly Glu His Leu Thr Ala Ala Val Glu Ser Ile Leu Tyr Leu Gly Gly 100 105 110 Asn Thr Lys Thr Gly Lys Ala Ile Gln Phe Ala Leu Asp Tyr Leu Phe 115 120 125 Ala Lys Ser Ser Arg Phe Leu Thr Lys Ile Ala Val Val Leu Thr Asp 130 135 140 Gly Lys Ser Gln Asp Asp Val Lys Asp Ala Ala Gln Ala Ala Arg Asp 145 150 155 160 Ser Lys Ile Thr Leu Phe Ala Ile Gly Val Gly Ser Glu Thr Glu Asp 165 170 175 Ala Glu Leu Arg Ala Ile Ala Asn Lys Pro Ser Ser Thr Tyr Val Phe 180 185 190 Tyr Val Glu Asp Tyr Ile Ala Ile Ser Lys Ile Arg Glu Val Met Lys 195 200 205 Gln Lys Leu Cys Glu Glu Ser Val Cys Pro Thr Arg Ile Pro Val Ala 210 215 220 Ala Arg Asp Glu Arg Gly Phe Asp Ile Leu Leu Gly Leu Asp Val Asn 225 230 235 240 Lys Lys Val Lys Lys Arg Ile Gln Leu Ser Pro Lys Lys Ile Lys Gly 245 250 255 Tyr Glu Val Thr Ser Lys Val Asp Leu Ser Glu Leu Thr Ser Asn Val 260 265 270 Phe Pro Glu Gly Leu Pro Pro Ser Tyr Val Phe Val Ser Thr Gln Arg 275 280 285 Phe Lys Val Lys Lys Ile Trp Asp Leu Trp Arg Ile Leu Thr Ile Asp 290 295 300 Gly Arg Pro Gln Ile Ala Val Thr Leu Asn Gly Val Asp Lys Ile Leu 305 310 315 320 Leu Phe Thr Thr Thr Ser Val Ile Asn Gly Ser Gln Val Val Thr Phe 325 330 335 Ala Asn Pro Gln Val Lys Thr Leu Phe Asp Glu Gly Trp His Gln Ile 340 345 350 Arg Leu Leu Val Thr Glu Gln Asp Val Thr Leu Tyr Ile Asp Asp Gln 355 360 365 Gln Ile Glu Asn Lys Pro Leu His Pro Val Leu Gly Ile Leu Ile Asn 370 375 380 Gly Gln Thr Gln Ile Gly Lys Tyr Ser Gly Lys Glu Glu Thr Val Gln 385 390 395 400 Phe Asp Val Gln Lys Leu Arg Ile Tyr Cys Asp Pro Glu Gln Asn Asn 405 410 415 Arg Glu Thr Ala Cys Glu Ile Pro Gly Phe Asn Gly Glu Cys Leu Asn 420 425 430 Gly Pro Ser Asp Val Gly Ser Thr Pro Ala Pro Cys Ile Cys Pro Pro 435 440 445 Gly Lys Pro Gly Leu Gln Gly Pro Lys Gly Asp Pro Gly Leu Pro Gly 450 455 460 Asn Pro Gly Tyr Pro Gly Gln Pro Gly Gln Asp Gly Lys Pro Gly Tyr 465 470 475 480 Gln Gly Ile Ala Gly Thr Pro Gly Val Pro Gly Ser Pro Gly Ile Gln 485 490 495 Gly Ala Arg Gly Leu Pro Gly Tyr Lys Gly Glu Pro Gly Arg Asp Gly 500 505 510 Asp Lys Gly Asp Arg Gly Leu Pro Gly Phe Pro Gly Leu His Gly Met 515 520 525 Pro Gly Ser Lys Gly Glu Met Gly Ala Lys Gly Asp Lys Gly Ser Pro 530 535 540 Gly Phe Tyr Gly Lys Lys Gly Ala Lys Gly Glu Lys Gly Asn Ala Gly 545 550 555 560 Phe Pro Gly Leu Pro Gly Pro Ala Gly Glu Pro Gly Arg His Gly Lys 565 570 575 Asp Gly Leu Met Gly Ser Pro Gly Phe Lys Gly Glu Ala Gly Ser Pro 580 585 590 Gly Ala Pro Gly Gln Asp Gly Thr Arg Gly Glu Pro Gly Ile Pro Gly 595 600 605 Phe Pro Gly Asn Arg Gly Leu Met Gly Gln Lys Gly Glu Ile Gly Pro 610 615 620 Pro Gly Gln Gln Gly Lys Lys Gly Ala Pro Gly Met Pro Gly Leu Met 625 630 635 640 Gly Ser Asn Gly Ser Pro Gly Gln Pro Gly Thr Pro Gly Ser Lys Gly 645 650 655 Ser Lys Gly Glu Pro Gly Ile Gln Gly Met Pro Gly Ala Ser Gly Leu 660 665 670 Lys Gly Glu Pro Gly Ala Thr Gly Ser Pro Gly Glu Pro Gly Tyr Met 675 680 685 Gly Leu Pro Gly Ile Gln Gly Lys Lys Gly Asp Lys Gly Asn Gln Gly 690 695 700 Glu Lys Gly Ile Gln Gly Gln Lys Gly Glu Asn Gly Arg Gln Gly Ile 705 710 715 720 Pro Gly Gln Gln Gly Ile Gln Gly His His Gly Ala Lys Gly Glu Arg 725 730 735 Gly Glu Lys Gly Glu Pro Gly Val Arg Gly Ala Ile Gly Ser Lys Gly 740 745 750 Glu Ser Gly Val Asp Gly Leu Met Gly Pro Ala Gly Pro Lys Gly Gln 755 760 765 Pro Gly Asp Pro Gly Pro Gln Gly Pro Pro Gly Leu Asp Gly Lys Pro 770 775 780 Gly Arg Glu Phe Ser Glu Gln Phe Ile Arg Gln Val Cys Thr Asp Val 785 790 795 800 Ile Arg Ala Gln Leu Pro Val Leu Leu Gln Ser Gly Arg Ile Arg Asn 805 810 815 Cys Asp His Cys Leu Ser Gln His Gly Ser Pro Gly Ile Pro Gly Pro 820 825 830 Pro Gly Pro Ile Gly Pro Glu Gly Pro Arg Gly Leu Pro Gly Leu Pro 835 840 845 Gly Arg Asp Gly Val Pro Gly Leu Val Gly Val Pro Gly Arg Pro Gly 850 855 860 Val Arg Gly Leu Lys Gly Leu Pro Gly Arg Asn Gly Glu Lys Gly Ser 865 870 875 880 Gln Gly Phe Gly Tyr Pro Gly Glu Gln Gly Pro Pro Gly Pro Pro Gly 885 890 895 Pro Glu Gly Pro Pro Gly Ile Ser Lys Glu Gly Pro Pro Gly Asp Pro 900 905 910 Gly Leu Pro Gly Lys Asp Gly Asp His Gly Lys Pro Gly Ile Gln Gly 915 920 925 Gln Pro Gly Pro Pro Gly Ile Cys Asp Pro Ser Leu Cys Phe Ser Val 930 935 940 Ile Ala Arg Arg Asp Pro Phe Arg Lys Gly Pro Asn Tyr 945 950 955 <210> 6 <211> 734 <212> PRT <213> Homo sapiens <400> 6 Met Trp Gly Leu Leu Leu Ala Leu Ala Ala Phe Ala Pro Ala Val Gly 1 5 10 15 Pro Ala Leu Gly Ala Pro Arg Asn Ser Val Leu Gly Leu Ala Gln Pro 20 25 30 Gly Thr Thr Lys Val Pro Gly Ser Thr Pro Ala Leu His Ser Ser Pro 35 40 45 Ala Gln Pro Pro Ala Glu Thr Ala Asn Gly Thr Ser Glu Gln His Val 50 55 60 Arg Ile Arg Val Ile Lys Lys Lys Lys Val Ile Met Lys Lys Arg Lys 65 70 75 80 Lys Leu Thr Leu Thr Arg Pro Thr Pro Leu Val Thr Ala Gly Pro Leu 85 90 95 Val Thr Pro Thr Pro Ala Gly Thr Leu Asp Pro Ala Glu Lys Gln Glu 100 105 110 Thr Gly Cys Pro Pro Leu Gly Leu Glu Ser Leu Arg Val Ser Asp Ser 115 120 125 Arg Leu Glu Ala Ser Ser Ser Gln Ser Phe Gly Leu Gly Pro His Arg 130 135 140 Gly Arg Leu Asn Ile Gln Ser Gly Leu Glu Asp Gly Asp Leu Tyr Asp 145 150 155 160 Gly Ala Trp Cys Ala Glu Glu Gln Asp Ala Asp Pro Trp Phe Gln Val 165 170 175 Asp Ala Gly His Pro Thr Arg Phe Ser Gly Val Ile Thr Gln Gly Arg 180 185 190 Asn Ser Val Trp Arg Tyr Asp Trp Val Thr Ser Tyr Lys Val Gln Phe 195 200 205 Ser Asn Asp Ser Arg Thr Trp Trp Gly Ser Arg Asn His Ser Ser Gly 210 215 220 Met Asp Ala Val Phe Pro Ala Asn Ser Asp Pro Glu Thr Pro Val Leu 225 230 235 240 Asn Leu Leu Pro Glu Pro Gln Val Ala Arg Phe Ile Arg Leu Leu Pro 245 250 255 Gln Thr Trp Leu Gln Gly Gly Ala Pro Cys Leu Arg Ala Glu Ile Leu 260 265 270 Ala Cys Pro Val Ser Asp Pro Asn Asp Leu Phe Leu Glu Ala Pro Ala 275 280 285 Ser Gly Ser Ser Asp Pro Leu Asp Phe Gln His His Asn Tyr Lys Ala 290 295 300 Met Arg Lys Leu Met Lys Gln Val Gln Glu Gln Cys Pro Asn Ile Thr 305 310 315 320 Arg Ile Tyr Ser Ile Gly Lys Ser Tyr Gln Gly Leu Lys Leu Tyr Val 325 330 335 Met Glu Met Ser Asp Lys Pro Gly Glu His Glu Leu Gly Glu Pro Glu 340 345 350 Val Arg Tyr Val Ala Gly Met His Gly Asn Glu Ala Leu Gly Arg Glu 355 360 365 Leu Leu Leu Leu Leu Met Gln Phe Leu Cys His Glu Phe Leu Arg Gly 370 375 380 Asn Pro Arg Val Thr Arg Leu Leu Ser Glu Met Arg Ile His Leu Leu 385 390 395 400 Pro Ser Met Asn Pro Asp Gly Tyr Glu Ile Ala Tyr His Arg Gly Ser 405 410 415 Glu Leu Val Gly Trp Ala Glu Gly Arg Trp Asn Asn Gln Ser Ile Asp 420 425 430 Leu Asn His Asn Phe Ala Asp Leu Asn Thr Pro Leu Trp Glu Ala Gln 435 440 445 Asp Asp Gly Lys Val Pro His Ile Val Pro Asn His His Leu Pro Leu 450 455 460 Pro Thr Tyr Tyr Thr Leu Pro Asn Ala Thr Val Ala Pro Glu Thr Arg 465 470 475 480 Ala Val Ile Lys Trp Met Lys Arg Ile Pro Phe Val Leu Ser Ala Asn 485 490 495 Leu His Gly Gly Glu Leu Val Val Ser Tyr Pro Phe Asp Met Thr Arg 500 505 510 Thr Pro Trp Ala Ala Arg Glu Leu Thr Pro Thr Pro Asp Asp Ala Val 515 520 525 Phe Arg Trp Leu Ser Thr Val Tyr Ala Gly Ser Asn Leu Ala Met Gln 530 535 540 Asp Thr Ser Arg Arg Pro Cys His Ser Gln Asp Phe Ser Val His Gly 545 550 555 560 Asn Ile Ile Asn Gly Ala Asp Trp His Thr Val Pro Gly Ser Met Asn 565 570 575 Asp Phe Ser Tyr Leu His Thr Asn Cys Phe Glu Val Thr Val Glu Leu 580 585 590 Ser Cys Asp Lys Phe Pro His Glu Asn Glu Leu Pro Gln Glu Trp Glu 595 600 605 Asn Asn Lys Asp Ala Leu Leu Thr Tyr Leu Glu Gln Val Arg Met Gly 610 615 620 Ile Ala Gly Val Val Arg Asp Lys Asp Thr Glu Leu Gly Ile Ala Asp 625 630 635 640 Ala Val Ile Ala Val Asp Gly Ile Asn His Asp Val Thr Thr Ala Trp 645 650 655 Gly Gly Asp Tyr Trp Arg Leu Leu Thr Pro Gly Asp Tyr Met Val Thr 660 665 670 Ala Ser Ala Glu Gly Tyr His Ser Val Thr Arg Asn Cys Arg Val Thr 675 680 685 Phe Glu Glu Gly Pro Phe Pro Cys Asn Phe Val Leu Thr Lys Thr Pro 690 695 700 Lys Gln Arg Leu Arg Glu Leu Leu Ala Ala Gly Ala Lys Val Pro Pro 705 710 715 720 Asp Leu Arg Arg Arg Leu Glu Arg Leu Arg Gly Gln Lys Asp 725 730 <210> 7 <211> 466 <212> PRT <213> Homo sapiens <400> 7 Met Ala Leu Leu Thr Ala Ala Ala Arg Leu Leu Gly Thr Lys Asn Ala 1 5 10 15 Ser Cys Leu Val Leu Ala Ala Arg His Ala Ser Ala Ser Ser Thr Asn 20 25 30 Leu Lys Asp Ile Leu Ala Asp Leu Ile Pro Lys Glu Gln Ala Arg Ile 35 40 45 Lys Thr Phe Arg Gln Gln His Gly Lys Thr Val Val Gly Gln Ile Thr 50 55 60 Val Asp Met Met Tyr Gly Gly Met Arg Gly Met Lys Gly Leu Val Tyr 65 70 75 80 Glu Thr Ser Val Leu Asp Pro Asp Glu Gly Ile Arg Phe Arg Gly Phe 85 90 95 Ser Ile Pro Glu Cys Gln Lys Leu Leu Pro Lys Ala Lys Gly Gly Glu 100 105 110 Glu Pro Leu Pro Glu Gly Leu Phe Trp Leu Leu Val Thr Gly His Ile 115 120 125 Pro Thr Glu Glu Gln Val Ser Trp Leu Ser Lys Glu Trp Ala Lys Arg 130 135 140 Ala Ala Leu Pro Ser His Val Val Thr Met Leu Asp Asn Phe Pro Thr 145 150 155 160 Asn Leu His Pro Met Ser Gln Leu Ser Ala Ala Val Thr Ala Leu Asn 165 170 175 Ser Glu Ser Asn Phe Ala Arg Ala Tyr Ala Gln Gly Ile Ser Arg Thr 180 185 190 Lys Tyr Trp Glu Leu Ile Tyr Glu Asp Ser Met Asp Leu Ile Ala Lys 195 200 205 Leu Pro Cys Val Ala Ala Lys Ile Tyr Arg Asn Leu Tyr Arg Glu Gly 210 215 220 Ser Gly Ile Gly Ala Ile Asp Ser Asn Leu Asp Trp Ser His Asn Phe 225 230 235 240 Thr Asn Met Leu Gly Tyr Thr Asp His Gln Phe Thr Glu Leu Thr Arg 245 250 255 Leu Tyr Leu Thr Ile His Ser Asp His Glu Gly Gly Asn Val Ser Ala 260 265 270 His Thr Ser His Leu Val Gly Ser Ala Leu Ser Asp Pro Tyr Leu Ser 275 280 285 Phe Ala Ala Ala Met Asn Gly Leu Ala Gly Pro Leu His Gly Leu Ala 290 295 300 Asn Gln Glu Val Leu Val Trp Leu Thr Gln Leu Gln Lys Glu Val Gly 305 310 315 320 Lys Asp Val Ser Asp Glu Lys Leu Arg Asp Tyr Ile Trp Asn Thr Leu 325 330 335 Asn Ser Gly Arg Val Val Pro Gly Tyr Gly His Ala Val Leu Arg Lys 340 345 350 Thr Asp Pro Arg Tyr Thr Cys Gln Arg Glu Phe Ala Leu Lys His Leu 355 360 365 Pro Asn Asp Pro Met Phe Lys Leu Val Ala Gln Leu Tyr Lys Ile Val 370 375 380 Pro Asn Val Leu Leu Glu Gln Gly Lys Ala Lys Asn Pro Trp Pro Asn 385 390 395 400 Val Asp Ala His Ser Gly Val Leu Leu Gln Tyr Tyr Gly Met Thr Glu 405 410 415 Met Asn Tyr Tyr Thr Val Leu Phe Gly Val Ser Arg Ala Leu Gly Val 420 425 430 Leu Ala Gln Leu Ile Trp Ser Arg Ala Leu Gly Phe Pro Leu Glu Arg 435 440 445 Pro Lys Ser Met Ser Thr Glu Gly Leu Met Lys Phe Val Asp Ser Lys 450 455 460 Ser Gly 465 <210> 8 <211> 396 <212> PRT <213> Homo sapiens <400> 8 Met Lys Thr Leu Leu Leu Leu Leu Leu Val Leu Leu Glu Leu Gly Glu 1 5 10 15 Ala Gln Gly Ser Leu His Arg Val Pro Leu Arg Arg His Pro Ser Leu 20 25 30 Lys Lys Lys Leu Arg Ala Arg Ser Gln Leu Ser Glu Phe Trp Lys Ser 35 40 45 His Asn Leu Asp Met Ile Gln Phe Thr Glu Ser Cys Ser Met Asp Gln 50 55 60 Ser Ala Lys Glu Pro Leu Ile Asn Tyr Leu Asp Met Glu Tyr Phe Gly 65 70 75 80 Thr Ile Ser Ile Gly Ser Pro Pro Gln Asn Phe Thr Val Ile Phe Asp 85 90 95 Thr Gly Ser Ser Asn Leu Trp Val Pro Ser Val Tyr Cys Thr Ser Pro 100 105 110 Ala Cys Lys Thr His Ser Arg Phe Gln Pro Ser Gln Ser Ser Thr Tyr 115 120 125 Ser Gln Pro Gly Gln Ser Phe Ser Ile Gln Tyr Gly Thr Gly Ser Leu 130 135 140 Ser Gly Ile Ile Gly Ala Asp Gln Val Ser Val Glu Gly Leu Thr Val 145 150 155 160 Val Gly Gln Gln Phe Gly Glu Ser Val Thr Glu Pro Gly Gln Thr Phe 165 170 175 Val Asp Ala Glu Phe Asp Gly Ile Leu Gly Leu Gly Tyr Pro Ser Leu 180 185 190 Ala Val Gly Gly Val Thr Pro Val Phe Asp Asn Met Met Ala Gln Asn 195 200 205 Leu Val Asp Leu Pro Met Phe Ser Val Tyr Met Ser Ser Asn Pro Glu 210 215 220 Gly Gly Ala Gly Ser Glu Leu Ile Phe Gly Gly Tyr Asp His Ser His 225 230 235 240 Phe Ser Gly Ser Leu Asn Trp Val Pro Val Thr Lys Gln Ala Tyr Trp 245 250 255 Gln Ile Ala Leu Asp Asn Ile Gln Val Gly Gly Thr Val Met Phe Cys 260 265 270 Ser Glu Gly Cys Gln Ala Ile Val Asp Thr Gly Thr Ser Leu Ile Thr 275 280 285 Gly Pro Ser Asp Lys Ile Lys Gln Leu Gln Asn Ala Ile Gly Ala Ala 290 295 300 Pro Val Asp Gly Glu Tyr Ala Val Glu Cys Ala Asn Leu Asn Val Met 305 310 315 320 Pro Asp Val Thr Phe Thr Ile Asn Gly Val Pro Tyr Thr Leu Ser Pro 325 330 335 Thr Ala Tyr Thr Leu Leu Asp Phe Val Asp Gly Met Gln Phe Cys Ser 340 345 350 Ser Gly Phe Gln Gly Leu Asp Ile His Pro Pro Ala Gly Pro Leu Trp 355 360 365 Ile Leu Gly Asp Val Phe Ile Arg Gln Phe Tyr Ser Val Phe Asp Arg 370 375 380 Gly Asn Asn Arg Val Gly Leu Ala Pro Ala Val Pro 385 390 395 <210> 9 <211> 429 <212> PRT <213> Homo sapiens <400> 9 Met Leu Pro Arg Leu Leu Leu Leu Ile Cys Ala Pro Leu Cys Glu Pro 1 5 10 15 Ala Glu Leu Phe Leu Ile Ala Ser Pro Ser His Pro Thr Glu Gly Ser 20 25 30 Pro Val Thr Leu Thr Cys Lys Met Pro Phe Leu Gln Ser Ser Asp Ala 35 40 45 Gln Phe Gln Phe Cys Phe Phe Arg Asp Thr Arg Ala Leu Gly Pro Gly 50 55 60 Trp Ser Ser Ser Pro Lys Leu Gln Ile Ala Ala Met Trp Lys Glu Asp 65 70 75 80 Thr Gly Ser Tyr Trp Cys Glu Ala Gln Thr Met Ala Ser Lys Val Leu 85 90 95 Arg Ser Arg Arg Ser Gln Ile Asn Val His Arg Val Pro Val Ala Asp 100 105 110 Val Ser Leu Glu Thr Gln Pro Pro Gly Gly Gln Val Met Glu Gly Asp 115 120 125 Arg Leu Val Leu Ile Cys Ser Val Ala Met Gly Thr Gly Asp Ile Thr 130 135 140 Phe Leu Trp Tyr Lys Gly Ala Val Gly Leu Asn Leu Gln Ser Lys Thr 145 150 155 160 Gln Arg Ser Leu Thr Ala Glu Tyr Glu Ile Pro Ser Val Arg Glu Ser 165 170 175 Asp Ala Glu Gln Tyr Tyr Cys Val Ala Glu Asn Gly Tyr Gly Pro Ser 180 185 190 Pro Ser Gly Leu Val Ser Ile Thr Val Arg Ile Pro Val Ser Arg Pro 195 200 205 Ile Leu Met Leu Arg Ala Pro Arg Ala Gln Ala Ala Val Glu Asp Val 210 215 220 Leu Glu Leu His Cys Glu Ala Leu Arg Gly Ser Pro Pro Ile Leu Tyr 225 230 235 240 Trp Phe Tyr His Glu Asp Ile Thr Leu Gly Ser Arg Ser Ala Pro Ser 245 250 255 Gly Gly Gly Ala Ser Phe Asn Leu Ser Leu Thr Glu Glu His Ser Gly 260 265 270 Asn Tyr Ser Cys Glu Ala Asn Asn Gly Leu Gly Ala Gln Arg Ser Glu 275 280 285 Ala Val Thr Leu Asn Phe Thr Val Pro Thr Gly Ala Arg Ser Asn His 290 295 300 Leu Thr Ser Gly Val Ile Glu Gly Leu Leu Ser Thr Leu Gly Pro Ala 305 310 315 320 Thr Val Ala Leu Leu Phe Cys Tyr Gly Leu Lys Arg Lys Ile Gly Arg 325 330 335 Arg Ser Ala Arg Asp Pro Leu Arg Ser Leu Pro Ser Pro Leu Pro Gln 340 345 350 Glu Phe Thr Tyr Leu Asn Ser Pro Thr Pro Gly Gln Leu Gln Pro Ile 355 360 365 Tyr Glu Asn Val Asn Val Val Ser Gly Asp Glu Val Tyr Ser Leu Ala 370 375 380 Tyr Tyr Asn Gln Pro Glu Gln Glu Ser Val Ala Ala Glu Thr Leu Gly 385 390 395 400 Thr His Met Glu Asp Lys Val Ser Leu Asp Ile Tyr Ser Arg Leu Arg 405 410 415 Lys Ala Asn Ile Thr Asp Val Asp Tyr Glu Asp Ala Met 420 425 <210> 10 <211> 620 <212> PRT <213> Homo sapiens <400> 10 Met Gln Val Ser Lys Arg Met Leu Ala Gly Gly Val Arg Ser Met Pro 1 5 10 15 Ser Pro Leu Leu Ala Cys Trp Gln Pro Ile Leu Leu Leu Val Leu Gly 20 25 30 Ser Val Leu Ser Gly Ser Ala Thr Gly Cys Pro Pro Arg Cys Glu Cys 35 40 45 Ser Ala Gln Asp Arg Ala Val Leu Cys His Arg Lys Arg Phe Val Ala 50 55 60 Val Pro Glu Gly Ile Pro Thr Glu Thr Arg Leu Leu Asp Leu Gly Lys 65 70 75 80 Asn Arg Ile Lys Thr Leu Asn Gln Asp Glu Phe Ala Ser Phe Pro His 85 90 95 Leu Glu Glu Leu Glu Leu Asn Glu Asn Ile Val Ser Ala Val Glu Pro 100 105 110 Gly Ala Phe Asn Asn Leu Phe Asn Leu Arg Thr Leu Gly Leu Arg Ser 115 120 125 Asn Arg Leu Lys Leu Ile Pro Leu Gly Val Phe Thr Gly Leu Ser Asn 130 135 140 Leu Thr Lys Leu Asp Ile Ser Glu Asn Lys Ile Val Ile Leu Leu Asp 145 150 155 160 Tyr Met Phe Gln Asp Leu Tyr Asn Leu Lys Ser Leu Glu Val Gly Asp 165 170 175 Asn Asp Leu Val Tyr Ile Ser His Arg Ala Phe Ser Gly Leu Asn Ser 180 185 190 Leu Glu Gln Leu Thr Leu Glu Lys Cys Asn Leu Thr Ser Ile Pro Thr 195 200 205 Glu Ala Leu Ser His Leu His Gly Leu Ile Val Leu Arg Leu Arg His 210 215 220 Leu Asn Ile Asn Ala Ile Arg Asp Tyr Ser Phe Lys Arg Leu Tyr Arg 225 230 235 240 Leu Lys Val Leu Glu Ile Ser His Trp Pro Tyr Leu Asp Thr Met Thr 245 250 255 Pro Asn Cys Leu Tyr Gly Leu Asn Leu Thr Ser Leu Ser Ile Thr His 260 265 270 Cys Asn Leu Thr Ala Val Pro Tyr Leu Ala Val Arg His Leu Val Tyr 275 280 285 Leu Arg Phe Leu Asn Leu Ser Tyr Asn Pro Ile Ser Thr Ile Glu Gly 290 295 300 Ser Met Leu His Glu Leu Leu Arg Leu Gln Glu Ile Gln Leu Val Gly 305 310 315 320 Gly Gln Leu Ala Val Val Glu Pro Tyr Ala Phe Arg Gly Leu Asn Tyr 325 330 335 Leu Arg Val Leu Asn Val Ser Gly Asn Gln Leu Thr Thr Leu Glu Glu 340 345 350 Ser Val Phe His Ser Val Gly Asn Leu Glu Thr Leu Ile Leu Asp Ser 355 360 365 Asn Pro Leu Ala Cys Asp Cys Arg Leu Leu Trp Val Phe Arg Arg Arg 370 375 380 Trp Arg Leu Asn Phe Asn Arg Gln Gln Pro Thr Cys Ala Thr Pro Glu 385 390 395 400 Phe Val Gln Gly Lys Glu Phe Lys Asp Phe Pro Asp Val Leu Leu Pro 405 410 415 Asn Tyr Phe Thr Cys Arg Arg Ala Arg Ile Arg Asp Arg Lys Ala Gln 420 425 430 Gln Val Phe Val Asp Glu Gly His Thr Val Gln Phe Val Cys Arg Ala 435 440 445 Asp Gly Asp Pro Pro Pro Ala Ile Leu Trp Leu Ser Pro Arg Lys His 450 455 460 Leu Val Ser Ala Lys Ser Asn Gly Arg Leu Thr Val Phe Pro Asp Gly 465 470 475 480 Thr Leu Glu Val Arg Tyr Ala Gln Val Gln Asp Asn Gly Thr Tyr Leu 485 490 495 Cys Ile Ala Ala Asn Ala Gly Gly Asn Asp Ser Met Pro Ala His Leu 500 505 510 His Val Arg Ser Tyr Ser Pro Asp Trp Pro His Gln Pro Asn Lys Thr 515 520 525 Phe Ala Phe Ile Ser Asn Gln Pro Gly Glu Gly Glu Ala Asn Ser Thr 530 535 540 Arg Ala Thr Val Pro Phe Pro Phe Asp Ile Lys Thr Leu Ile Ile Ala 545 550 555 560 Thr Thr Met Gly Phe Ile Ser Phe Leu Gly Val Val Leu Phe Cys Leu 565 570 575 Val Leu Leu Phe Leu Trp Ser Arg Gly Lys Gly Asn Thr Lys His Asn 580 585 590 Ile Glu Ile Glu Tyr Val Pro Arg Lys Ser Asp Ala Gly Ile Ser Ser 595 600 605 Ala Asp Ala Pro Arg Lys Phe Asn Met Lys Met Ile 610 615 620 <210> 11 <211> 1972 <212> PRT <213> Homo sapiens <400> 11 Met Ala Gln Lys Gly Gln Leu Ser Asp Asp Glu Lys Phe Leu Phe Val 1 5 10 15 Asp Lys Asn Phe Ile Asn Ser Pro Val Ala Gln Ala Asp Trp Ala Ala 20 25 30 Lys Arg Leu Val Trp Val Pro Ser Glu Lys Gln Gly Phe Glu Ala Ala 35 40 45 Ser Ile Lys Glu Glu Lys Gly Asp Glu Val Val Val Glu Leu Val Glu 50 55 60 Asn Gly Lys Lys Val Thr Val Gly Lys Asp Asp Ile Gln Lys Met Asn 65 70 75 80 Pro Pro Lys Phe Ser Lys Val Glu Asp Met Ala Glu Leu Thr Cys Leu 85 90 95 Asn Glu Ala Ser Val Leu His Asn Leu Arg Glu Arg Tyr Phe Ser Gly 100 105 110 Leu Ile Tyr Thr Tyr Ser Gly Leu Phe Cys Val Val Val Asn Pro Tyr 115 120 125 Lys His Leu Pro Ile Tyr Ser Glu Lys Ile Val Asp Met Tyr Lys Gly 130 135 140 Lys Lys Arg His Glu Met Pro Pro His Ile Tyr Ala Ile Ala Asp Thr 145 150 155 160 Ala Tyr Arg Ser Met Leu Gln Asp Arg Glu Asp Gln Ser Ile Leu Cys 165 170 175 Thr Gly Glu Ser Gly Ala Gly Lys Thr Glu Asn Thr Lys Lys Val Ile 180 185 190 Gln Tyr Leu Ala Val Val Ala Ser Ser His Lys Gly Lys Lys Asp Thr 195 200 205 Ser Ile Thr Gly Glu Leu Glu Lys Gln Leu Leu Gln Ala Asn Pro Ile 210 215 220 Leu Glu Ala Phe Gly Asn Ala Lys Thr Val Lys Asn Asp Asn Ser Ser 225 230 235 240 Arg Phe Gly Lys Phe Ile Arg Ile Asn Phe Asp Val Thr Gly Tyr Ile 245 250 255 Val Gly Ala Asn Ile Glu Thr Tyr Leu Leu Glu Lys Ser Arg Ala Ile 260 265 270 Arg Gln Ala Arg Asp Glu Arg Thr Phe His Ile Phe Tyr Tyr Met Ile 275 280 285 Ala Gly Ala Lys Glu Lys Met Arg Ser Asp Leu Leu Leu Glu Gly Phe 290 295 300 Asn Asn Tyr Thr Phe Leu Ser Asn Gly Phe Val Pro Ile Pro Ala Ala 305 310 315 320 Gln Asp Asp Glu Met Phe Gln Glu Thr Val Glu Ala Met Ala Ile Met 325 330 335 Gly Phe Ser Glu Glu Glu Gln Leu Ser Ile Leu Lys Val Val Ser Ser 340 345 350 Val Leu Gln Leu Gly Asn Ile Val Phe Lys Lys Glu Arg Asn Thr Asp 355 360 365 Gln Ala Ser Met Pro Asp Asn Thr Ala Ala Gln Lys Val Cys His Leu 370 375 380 Met Gly Ile Asn Val Thr Asp Phe Thr Arg Ser Ile Leu Thr Pro Arg 385 390 395 400 Ile Lys Val Gly Arg Asp Val Val Gln Lys Ala Gln Thr Lys Glu Gln 405 410 415 Ala Asp Phe Ala Val Glu Ala Leu Ala Lys Ala Thr Tyr Glu Arg Leu 420 425 430 Phe Arg Trp Ile Leu Thr Arg Val Asn Lys Ala Leu Asp Lys Thr His 435 440 445 Arg Gln Gly Ala Ser Phe Leu Gly Ile Leu Asp Ile Ala Gly Phe Glu 450 455 460 Ile Phe Glu Val Asn Ser Phe Glu Gln Leu Cys Ile Asn Tyr Thr Asn 465 470 475 480 Glu Lys Leu Gln Gln Leu Phe Asn His Thr Met Phe Ile Leu Glu Gln 485 490 495 Glu Glu Tyr Gln Arg Glu Gly Ile Glu Trp Asn Phe Ile Asp Phe Gly 500 505 510 Leu Asp Leu Gln Pro Cys Ile Glu Leu Ile Glu Arg Pro Asn Asn Pro 515 520 525 Pro Gly Val Leu Ala Leu Leu Asp Glu Glu Cys Trp Phe Pro Lys Ala 530 535 540 Thr Asp Lys Ser Phe Val Glu Lys Leu Cys Thr Glu Gln Gly Ser His 545 550 555 560 Pro Lys Phe Gln Lys Pro Lys Gln Leu Lys Asp Lys Thr Glu Phe Ser 565 570 575 Ile Ile His Tyr Ala Gly Lys Val Asp Tyr Asn Ala Ser Ala Trp Leu 580 585 590 Thr Lys Asn Met Asp Pro Leu Asn Asp Asn Val Thr Ser Leu Leu Asn 595 600 605 Ala Ser Ser Asp Lys Phe Val Ala Asp Leu Trp Lys Asp Val Asp Arg 610 615 620 Ile Val Gly Leu Asp Gln Met Ala Lys Met Thr Glu Ser Ser Leu Pro 625 630 635 640 Ser Ala Ser Lys Thr Lys Lys Gly Met Phe Arg Thr Val Gly Gln Leu 645 650 655 Tyr Lys Glu Gln Leu Gly Lys Leu Met Thr Thr Leu Arg Asn Thr Thr 660 665 670 Pro Asn Phe Val Arg Cys Ile Ile Pro Asn His Glu Lys Arg Ser Gly 675 680 685 Lys Leu Asp Ala Phe Leu Val Leu Glu Gln Leu Arg Cys Asn Gly Val 690 695 700 Leu Glu Gly Ile Arg Ile Cys Arg Gln Gly Phe Pro Asn Arg Ile Val 705 710 715 720 Phe Gln Glu Phe Arg Gln Arg Tyr Glu Ile Leu Ala Ala Asn Ala Ile 725 730 735 Pro Lys Gly Phe Met Asp Gly Lys Gln Ala Cys Ile Leu Met Ile Lys 740 745 750 Ala Leu Glu Leu Asp Pro Asn Leu Tyr Arg Ile Gly Gln Ser Lys Ile 755 760 765 Phe Phe Arg Thr Gly Val Leu Ala His Leu Glu Glu Glu Arg Asp Leu 770 775 780 Lys Ile Thr Asp Val Ile Met Ala Phe Gln Ala Met Cys Arg Gly Tyr 785 790 795 800 Leu Ala Arg Lys Ala Phe Ala Lys Arg Gln Gln Gln Leu Thr Ala Met 805 810 815 Lys Val Ile Gln Arg Asn Cys Ala Ala Tyr Leu Lys Leu Arg Asn Trp 820 825 830 Gln Trp Trp Arg Leu Phe Thr Lys Val Lys Pro Leu Leu Gln Val Thr 835 840 845 Arg Gln Glu Glu Glu Met Gln Ala Lys Glu Asp Glu Leu Gln Lys Thr 850 855 860 Lys Glu Arg Gln Gln Lys Ala Glu Asn Glu Leu Lys Glu Leu Glu Gln 865 870 875 880 Lys His Ser Gln Leu Thr Glu Glu Lys Asn Leu Leu Gln Glu Gln Leu 885 890 895 Gln Ala Glu Thr Glu Leu Tyr Ala Glu Ala Glu Glu Met Arg Val Arg 900 905 910 Leu Ala Ala Lys Lys Gln Glu Leu Glu Glu Ile Leu His Glu Met Glu 915 920 925 Ala Arg Leu Glu Glu Glu Glu Asp Arg Gly Gln Gln Leu Gln Ala Glu 930 935 940 Arg Lys Lys Met Ala Gln Gln Met Leu Asp Leu Glu Glu Gln Leu Glu 945 950 955 960 Glu Glu Glu Ala Ala Arg Gln Lys Leu Gln Leu Glu Lys Val Thr Ala 965 970 975 Glu Ala Lys Ile Lys Lys Leu Glu Asp Glu Ile Leu Val Met Asp Asp 980 985 990 Gln Asn Asn Lys Leu Ser Lys Glu Arg Lys Leu Leu Glu Glu Arg Ile 995 1000 1005 Ser Asp Leu Thr Thr Asn Leu Ala Glu Glu Glu Glu Lys Ala Lys Asn 1010 1015 1020 Leu Thr Lys Leu Lys Asn Lys His Glu Ser Met Ile Ser Glu Leu Glu 1025 1030 1035 1040 Val Arg Leu Lys Lys Glu Glu Lys Ser Arg Gln Glu Leu Glu Lys Leu 1045 1050 1055 Lys Arg Lys Leu Glu Gly Asp Ala Ser Asp Phe His Glu Gln Ile Ala 1060 1065 1070 Asp Leu Gln Ala Gln Ile Ala Glu Leu Lys Met Gln Leu Ala Lys Lys 1075 1080 1085 Glu Glu Glu Leu Gln Ala Ala Leu Ala Arg Leu Asp Asp Glu Ile Ala 1090 1095 1100 Gln Lys Asn Asn Ala Leu Lys Lys Ile Arg Glu Leu Glu Gly His Ile 1105 1110 1115 1120 Ser Asp Leu Gln Glu Asp Leu Asp Ser Glu Arg Ala Ala Arg Asn Lys 1125 1130 1135 Ala Glu Lys Gln Lys Arg Asp Leu Gly Glu Glu Leu Glu Ala Leu Lys 1140 1145 1150 Thr Glu Leu Glu Asp Thr Leu Asp Ser Thr Ala Thr Gln Gln Glu Leu 1155 1160 1165 Arg Ala Lys Arg Glu Gln Glu Val Thr Val Leu Lys Lys Ala Leu Asp 1170 1175 1180 Glu Glu Thr Arg Ser His Glu Ala Gln Val Gln Glu Met Arg Gln Lys 1185 1190 1195 1200 His Ala Gln Ala Val Glu Glu Leu Thr Glu Gln Leu Glu Gln Phe Lys 1205 1210 1215 Arg Ala Lys Ala Asn Leu Asp Lys Asn Lys Gln Thr Leu Glu Lys Glu 1220 1225 1230 Asn Ala Asp Leu Ala Gly Glu Leu Arg Val Leu Gly Gln Ala Lys Gln 1235 1240 1245 Glu Val Glu His Lys Lys Lys Lys Leu Glu Ala Gln Val Gln Glu Leu 1250 1255 1260 Gln Ser Lys Cys Ser Asp Gly Glu Arg Ala Arg Ala Glu Leu Asn Asp 1265 1270 1275 1280 Lys Val His Lys Leu Gln Asn Glu Val Glu Ser Val Thr Gly Met Leu 1285 1290 1295 Asn Glu Ala Glu Gly Lys Ala Ile Lys Leu Ala Lys Asp Val Ala Ser 1300 1305 1310 Leu Ser Ser Gln Leu Gln Asp Thr Gln Glu Leu Leu Gln Glu Glu Thr 1315 1320 1325 Arg Gln Lys Leu Asn Val Ser Thr Lys Leu Arg Gln Leu Glu Glu Glu 1330 1335 1340 Arg Asn Ser Leu Gln Asp Gln Leu Asp Glu Glu Met Glu Ala Lys Gln 1345 1350 1355 1360 Asn Leu Glu Arg His Ile Ser Thr Leu Asn Ile Gln Leu Ser Asp Ser 1365 1370 1375 Lys Lys Lys Leu Gln Asp Phe Ala Ser Thr Val Glu Ala Leu Glu Glu 1380 1385 1390 Gly Lys Lys Arg Phe Gln Lys Glu Ile Glu Asn Leu Thr Gln Gln Tyr 1395 1400 1405 Glu Glu Lys Ala Ala Ala Tyr Asp Lys Leu Glu Lys Thr Lys Asn Arg 1410 1415 1420 Leu Gln Gln Glu Leu Asp Asp Leu Val Val Asp Leu Asp Asn Gln Arg 1425 1430 1435 1440 Gln Leu Val Ser Asn Leu Glu Lys Lys Gln Arg Lys Phe Asp Gln Leu 1445 1450 1455 Leu Ala Glu Glu Lys Asn Ile Ser Ser Lys Tyr Ala Asp Glu Arg Asp 1460 1465 1470 Arg Ala Glu Ala Glu Ala Arg Glu Lys Glu Thr Lys Ala Leu Ser Leu 1475 1480 1485 Ala Arg Ala Leu Glu Glu Ala Leu Glu Ala Lys Glu Glu Leu Glu Arg 1490 1495 1500 Thr Asn Lys Met Leu Lys Ala Glu Met Glu Asp Leu Val Ser Ser Lys 1505 1510 1515 1520 Asp Asp Val Gly Lys Asn Val His Glu Leu Glu Lys Ser Lys Arg Ala 1525 1530 1535 Leu Glu Thr Gln Met Glu Glu Met Lys Thr Gln Leu Glu Glu Leu Glu 1540 1545 1550 Asp Glu Leu Gln Ala Thr Glu Asp Ala Lys Leu Arg Leu Glu Val Asn 1555 1560 1565 Met Gln Ala Leu Lys Gly Gln Phe Glu Arg Asp Leu Gln Ala Arg Asp 1570 1575 1580 Glu Gln Asn Glu Glu Lys Arg Arg Gln Leu Gln Arg Gln Leu His Glu 1585 1590 1595 1600 Tyr Glu Thr Glu Leu Glu Asp Glu Arg Lys Gln Arg Ala Leu Ala Ala 1605 1610 1615 Ala Ala Lys Lys Lys Leu Glu Gly Asp Leu Lys Asp Leu Glu Leu Gln 1620 1625 1630 Ala Asp Ser Ala Ile Lys Gly Arg Glu Glu Ala Ile Lys Gln Leu Arg 1635 1640 1645 Lys Leu Gln Ala Gln Met Lys Asp Phe Gln Arg Glu Leu Glu Asp Ala 1650 1655 1660 Arg Ala Ser Arg Asp Glu Ile Phe Ala Thr Ala Lys Glu Asn Glu Lys 1665 1670 1675 1680 Lys Ala Lys Ser Leu Glu Ala Asp Leu Met Gln Leu Gln Glu Asp Leu 1685 1690 1695 Ala Ala Ala Glu Arg Ala Arg Lys Gln Ala Asp Leu Glu Lys Glu Glu 1700 1705 1710 Leu Ala Glu Glu Leu Ala Ser Ser Leu Ser Gly Arg Asn Ala Leu Gln 1715 1720 1725 Asp Glu Lys Arg Arg Leu Glu Ala Arg Ile Ala Gln Leu Glu Glu Glu 1730 1735 1740 Leu Glu Glu Glu Gln Gly Asn Met Glu Ala Met Ser Asp Arg Val Arg 1745 1750 1755 1760 Lys Ala Thr Gln Gln Ala Glu Gln Leu Ser Asn Glu Leu Ala Thr Glu 1765 1770 1775 Arg Ser Thr Ala Gln Lys Asn Glu Ser Ala Arg Gln Gln Leu Glu Arg 1780 1785 1790 Gln Asn Lys Glu Leu Arg Ser Lys Leu His Glu Met Glu Gly Ala Val 1795 1800 1805 Lys Ser Lys Phe Lys Ser Thr Ile Ala Ala Leu Glu Ala Lys Ile Ala 1810 1815 1820 Gln Leu Glu Glu Gln Val Glu Gln Glu Ala Arg Glu Lys Gln Ala Ala 1825 1830 1835 1840 Thr Lys Ser Leu Lys Gln Lys Asp Lys Lys Leu Lys Glu Ile Leu Leu 1845 1850 1855 Gln Val Glu Asp Glu Arg Lys Met Ala Glu Gln Tyr Lys Glu Gln Ala 1860 1865 1870 Glu Lys Gly Asn Ala Arg Val Lys Gln Leu Lys Arg Gln Leu Glu Glu 1875 1880 1885 Ala Glu Glu Glu Ser Gln Arg Ile Asn Ala Asn Arg Arg Lys Leu Gln 1890 1895 1900 Arg Glu Leu Asp Glu Ala Thr Glu Ser Asn Glu Ala Met Gly Arg Glu 1905 1910 1915 1920 Val Asn Ala Leu Lys Ser Lys Leu Arg Arg Gly Asn Glu Thr Ser Phe 1925 1930 1935 Val Pro Ser Arg Arg Ser Gly Gly Arg Arg Val Ile Glu Asn Ala Asp 1940 1945 1950 Gly Ser Glu Glu Glu Thr Asp Thr Arg Asp Ala Asp Phe Asn Gly Thr 1955 1960 1965 Lys Ala Ser Glu 1970 <210> 12 <211> 434 <212> PRT <213> Homo sapiens <400> 12 Met Ser Ala Asp Gly Ala Glu Ala Asp Gly Ser Thr Gln Val Thr Val 1 5 10 15 Glu Glu Pro Val Gln Gln Pro Ser Val Val Asp Arg Val Ala Ser Met 20 25 30 Pro Leu Ile Ser Ser Thr Cys Asp Met Val Ser Ala Ala Tyr Ala Ser 35 40 45 Thr Lys Glu Ser Tyr Pro His Ile Lys Thr Val Cys Asp Ala Ala Glu 50 55 60 Lys Gly Val Arg Thr Leu Thr Ala Ala Ala Val Ser Gly Ala Gln Pro 65 70 75 80 Ile Leu Ser Lys Leu Glu Pro Gln Ile Ala Ser Ala Ser Glu Tyr Ala 85 90 95 His Arg Gly Leu Asp Lys Leu Glu Glu Asn Leu Pro Ile Leu Gln Gln 100 105 110 Pro Thr Glu Lys Val Leu Ala Asp Thr Lys Glu Leu Val Ser Ser Lys 115 120 125 Val Ser Gly Ala Gln Glu Met Val Ser Ser Ala Lys Asp Thr Val Ala 130 135 140 Thr Gln Leu Ser Glu Ala Val Asp Ala Thr Arg Gly Ala Val Gln Ser 145 150 155 160 Gly Val Asp Lys Thr Lys Ser Val Val Thr Gly Gly Val Gln Ser Val 165 170 175 Met Gly Ser Arg Leu Gly Gln Met Val Leu Ser Gly Val Asp Thr Val 180 185 190 Leu Gly Lys Ser Glu Glu Trp Ala Asp Asn His Leu Pro Leu Thr Asp 195 200 205 Ala Glu Leu Ala Arg Ile Ala Thr Ser Leu Asp Gly Phe Asp Val Ala 210 215 220 Ser Val Gln Gln Gln Arg Gln Glu Gln Ser Tyr Phe Val Arg Leu Gly 225 230 235 240 Ser Leu Ser Glu Arg Leu Arg Gln His Ala Tyr Glu His Ser Leu Gly 245 250 255 Lys Leu Arg Ala Thr Lys Gln Arg Ala Gln Glu Ala Leu Leu Gln Leu 260 265 270 Ser Gln Val Leu Ser Leu Met Glu Thr Val Lys Gln Gly Val Asp Gln 275 280 285 Lys Leu Val Glu Gly Gln Glu Lys Leu His Gln Met Trp Leu Ser Trp 290 295 300 Asn Gln Lys Gln Leu Gln Gly Pro Glu Lys Glu Pro Pro Lys Pro Glu 305 310 315 320 Gln Val Glu Ser Arg Ala Leu Thr Met Phe Arg Asp Ile Ala Gln Gln 325 330 335 Leu Gln Ala Thr Cys Thr Ser Leu Gly Ser Ser Ile Gln Gly Leu Pro 340 345 350 Thr Asn Val Lys Asp Gln Val Gln Gln Ala Arg Arg Gln Val Glu Asp 355 360 365 Leu Gln Ala Thr Phe Ser Ser Ile His Ser Phe Gln Asp Leu Ser Ser 370 375 380 Ser Ile Leu Ala Gln Ser Arg Glu Arg Val Ala Ser Ala Arg Glu Ala 385 390 395 400 Leu Asp His Met Val Glu Tyr Val Ala Gln Asn Thr Pro Val Thr Trp 405 410 415 Leu Val Gly Pro Phe Ala Pro Gly Ile Thr Glu Lys Ala Pro Glu Glu 420 425 430 Lys Lys <210> 13 <211> 51 <212> PRT <213> Homo sapiens <400> 13 Ala Gly Thr Ala Thr Cys Ala Thr Cys Ala Cys Thr Thr Cys Thr Cys 1 5 10 15 Cys Ala Cys Ala Ala Thr Gly Thr Gly Thr Thr Cys Thr Thr Ala Ala 20 25 30 Gly Gly Gly Cys Ala Gly Ala Ala Thr Thr Cys Cys Ala Gly Ala Ala 35 40 45 Cys Thr Thr 50 <210> 14 <211> 473 <212> PRT <213> Homo sapiens <400> 14 Met Gly Ala Val Leu Gly Val Phe Ser Leu Ala Ser Trp Val Pro Cys 1 5 10 15 Leu Cys Ser Gly Ala Ser Cys Leu Leu Cys Ser Cys Cys Pro Asn Ser 20 25 30 Lys Asn Ser Thr Val Thr Arg Leu Ile Tyr Ala Phe Ile Leu Leu Leu 35 40 45 Ser Thr Val Val Ser Tyr Ile Met Gln Arg Lys Glu Met Glu Thr Tyr 50 55 60 Leu Lys Lys Ile Pro Gly Phe Cys Glu Gly Gly Phe Lys Ile His Glu 65 70 75 80 Ala Asp Ile Asn Ala Asp Lys Asp Cys Asp Val Leu Val Gly Tyr Lys 85 90 95 Ala Val Tyr Arg Ile Ser Phe Ala Met Ala Ile Phe Phe Phe Val Phe 100 105 110 Ser Leu Leu Met Phe Lys Val Lys Thr Ser Lys Asp Leu Arg Ala Ala 115 120 125 Val His Asn Gly Phe Trp Phe Phe Lys Ile Ala Ala Leu Ile Gly Ile 130 135 140 Met Val Gly Ser Phe Tyr Ile Pro Gly Gly Tyr Phe Ser Ser Val Trp 145 150 155 160 Phe Val Val Gly Met Ile Gly Ala Ala Leu Phe Ile Leu Ile Gln Leu 165 170 175 Val Leu Leu Val Asp Phe Ala His Ser Trp Asn Glu Ser Trp Val Asn 180 185 190 Arg Met Glu Glu Gly Asn Pro Arg Leu Trp Tyr Ala Ala Leu Leu Ser 195 200 205 Phe Thr Ser Ala Phe Tyr Ile Leu Ser Ile Ile Cys Val Gly Leu Leu 210 215 220 Tyr Thr Tyr Tyr Thr Lys Pro Asp Gly Cys Thr Glu Asn Lys Phe Phe 225 230 235 240 Ile Ser Ile Asn Leu Ile Leu Cys Val Val Ala Ser Ile Ile Ser Ile 245 250 255 His Pro Lys Ile Gln Glu His Gln Pro Arg Ser Gly Leu Leu Gln Ser 260 265 270 Ser Leu Ile Thr Leu Tyr Thr Met Tyr Leu Thr Trp Ser Ala Met Ser 275 280 285 Asn Glu Pro Asp Arg Ser Cys Asn Pro Asn Leu Met Ser Phe Ile Thr 290 295 300 Arg Ile Thr Ala Pro Thr Leu Ala Pro Gly Asn Ser Thr Ala Val Val 305 310 315 320 Pro Thr Pro Thr Pro Pro Ser Lys Ser Gly Ser Leu Leu Asp Ser Asp 325 330 335 Asn Phe Ile Gly Leu Phe Val Phe Val Leu Cys Leu Leu Tyr Ser Ser 340 345 350 Ile Arg Thr Ser Thr Asn Ser Gln Val Asp Lys Leu Thr Leu Ser Gly 355 360 365 Ser Asp Ser Val Ile Leu Gly Asp Thr Thr Thr Ser Gly Ala Ser Asp 370 375 380 Glu Glu Asp Gly Gln Pro Arg Arg Ala Val Asp Asn Glu Lys Glu Gly 385 390 395 400 Val Gln Tyr Ser Tyr Ser Leu Phe His Leu Met Leu Cys Leu Ala Ser 405 410 415 Leu Tyr Ile Met Met Thr Leu Thr Ser Trp Tyr Ser Pro Asp Ala Lys 420 425 430 Phe Gln Ser Met Thr Ser Lys Trp Pro Ala Val Trp Val Lys Ile Ser 435 440 445 Ser Ser Trp Val Cys Leu Leu Leu Tyr Val Trp Thr Leu Val Ala Pro 450 455 460 Leu Val Leu Thr Ser Arg Asp Phe Ser 465 470 <210> 15 <211> 435 <212> PRT <213> Homo sapiens <400> 15 Met Glu Gly Gln Thr Pro Gly Ser Arg Gly Leu Pro Glu Lys Pro His 1 5 10 15 Pro Ala Thr Ala Ala Ala Thr Leu Ser Ser Met Gly Ala Val Phe Ile 20 25 30 Leu Met Lys Ser Ala Leu Gly Ala Gly Leu Leu Asn Phe Pro Trp Ala 35 40 45 Phe Ser Lys Ala Gly Gly Val Val Pro Ala Phe Leu Val Glu Leu Val 50 55 60 Ser Leu Val Phe Leu Ile Ser Gly Leu Val Ile Leu Gly Tyr Ala Ala 65 70 75 80 Ala Val Ser Gly Gln Ala Thr Tyr Gln Gly Val Val Arg Gly Leu Cys 85 90 95 Gly Pro Ala Ile Gly Lys Leu Cys Glu Ala Cys Phe Leu Leu Asn Leu 100 105 110 Leu Met Ile Ser Val Ala Phe Leu Arg Val Ile Gly Asp Gln Leu Glu 115 120 125 Lys Leu Cys Asp Ser Leu Leu Ser Gly Thr Pro Pro Ala Pro Gln Pro 130 135 140 Trp Tyr Ala Asp Gln Arg Phe Thr Leu Pro Leu Leu Ser Val Leu Val 145 150 155 160 Ile Leu Pro Leu Ser Ala Pro Arg Glu Ile Ala Phe Gln Lys Tyr Thr 165 170 175 Ser Ile Leu Gly Thr Leu Ala Ala Cys Tyr Leu Ala Leu Val Ile Thr 180 185 190 Val Gln Tyr Tyr Leu Trp Pro Gln Gly Leu Val Arg Glu Ser His Pro 195 200 205 Ser Leu Ser Pro Ala Ser Trp Thr Ser Val Phe Ser Val Phe Pro Thr 210 215 220 Ile Cys Phe Gly Phe Gln Cys His Glu Ala Ala Val Ser Ile Tyr Cys 225 230 235 240 Ser Met Arg Lys Arg Ser Leu Ser His Trp Ala Leu Val Ser Val Leu 245 250 255 Ser Leu Leu Ala Cys Cys Leu Ile Tyr Ser Leu Thr Gly Val Tyr Gly 260 265 270 Phe Leu Thr Phe Gly Thr Glu Val Ser Ala Asp Val Leu Met Ser Tyr 275 280 285 Pro Gly Asn Asp Met Val Ile Ile Val Ala Arg Val Leu Phe Ala Val 290 295 300 Ser Ile Val Thr Val Tyr Pro Ile Val Leu Phe Leu Gly Arg Ser Val 305 310 315 320 Met Gln Asp Phe Trp Arg Arg Ser Cys Leu Gly Gly Trp Gly Pro Ser 325 330 335 Ala Leu Ala Asp Pro Ser Gly Leu Trp Val Arg Met Pro Leu Thr Ile 340 345 350 Leu Trp Val Thr Val Thr Leu Ala Met Ala Leu Phe Met Pro Asp Leu 355 360 365 Ser Glu Ile Val Ser Ile Ile Gly Gly Ile Ser Ser Phe Phe Ile Phe 370 375 380 Ile Phe Pro Gly Leu Cys Leu Ile Cys Ala Met Gly Val Glu Pro Ile 385 390 395 400 Gly Pro Arg Val Lys Cys Cys Leu Glu Val Trp Gly Val Val Ser Val 405 410 415 Leu Val Gly Thr Phe Ile Phe Gly Gln Ser Thr Ala Ala Ala Val Trp 420 425 430 Glu Met Phe 435 <210> 16 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 16 gagtattttc tgcctcattt ctcagtttga ctgcctacca accatatttg 50 <210> 17 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 17 gagtattttc tgcctcattt ctcagtttga ctgcctacca accatatttg 50 <210> 18 <211> 51 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 18 agtatcatca cttctccaca atgtgttctt aagggcagaa ttccagaact t 51 <210> 19 <211> 47 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 19 tcgtgacatt ggagaccttg ctctgttctt ggaaatcctg ctcatgg 47 <210> 20 <211> 48 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 20 ggaagcaagt gtttcaactg ttccggaatg tttgttgtat gccttcat 48 <210> 21 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 21 ggtgggatcc tcttttcaca caagcagaag atcattaatt gggtcctgat 50 <210> 22 <211> 48 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 22 tctcagggag gctttcctct ggtgaacagg gaattgattc aagattgg 48 <210> 23 <211> 44 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 23 cgttgctggt tgaaatcccg tccaactaac aaatgccaaa ggga 44 <210> 24 <211> 46 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 24 cagataatcc agcaggagtg caaccaggca ctcactctta tgaatt 46 <210> 25 <211> 50 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 25 ccccacagtg agataataat gaccaactca ggaaaacagg aaaggaggtt 50 <210> 26 <211> 44 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 26 ctgctgagcg gcccagtaac tcaatggatt gtgcagacac tgag 44 <210> 27 <211> 46 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 27 agcatttcaa caaggcttac cactcccctg cagaattttt tttcct 46 <210> 28 <211> 43 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 28 gtattctggg aacgtcggag actggtaagt gtgggaacaa ggc 43 <210> 29 <211> 52 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 29 cctgtctctt atattcttat ggcccaatgc atttgatctg tgcagattga ta 52 <210> 30 <211> 49 <212> DNA_RNA <213> Homo sapiens <220> <223> Forward, Reverse Primer <400> 30 aaggaggcag aaggcatcag tctggtactt tgcttcccat tgtcttgga 49
Claims (7)
서열번호 8로 나타내는 CTSE의 아미노산 서열에서, T116M 및 P30L로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 9로 나타내는 FCRL1의 아미노산 서열에서, A74T, A284S, 및 A320V 로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 10로 나타내는 LINGO1의 아미노산 서열에서, F410I, A9V, V138I 및 P549H로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 11로 나타내는 MYH11의 아미노산 서열에서, A815T, E1888K, T975M, A732V, A1259V 및 A334V로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이고, R1609* 적어도 하나인 넌센스 돌연변이; 서열번호 12로 나타내는 PLIN3의 아미노산 서열에서, 프레임 시프트 돌연변이의 표기 방식은, 아미노산 종류(아미노산 위치)아미노산 종류fs*(아미노산 위치에서 하류 방향으로 정지 코돈까지의 뉴클레오티드 개수)이다. (프레임 시프트 삽입 돌연변이, 프레임 시프트 결실 돌연변이 모두 동일한 표기 방식이며, 이하에서는 설명을 생략함) Q263Rfs*14 및 Q174Lfs*48 중 적어도 하나인 프레임 시프트 결실(frame shift delete, FS del) 돌연변이고, A119V중 적어도 하나인 미스센스 돌연변이; 서열번호 13로 나타내는 POLR2B의 아미노산 서열에서, D45Y, R157W 및 Q948R로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 14로 나타내는 SERINC3의 아미노산 서열에서, I45S 및 D88V로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이; 서열번호 15로 나타내는 SLC38A8의 아미노산 서열에서, V193M 및 V61M로 이루어진 군으로부터 선택되는 적어도 하나인 미스센스 돌연변이로부터 선택되는 적어도 하나의 전립선암의 예후 진단을 위한 프라이머 세트를 포함하는 전립선암의 예후 진단용 키트.The method according to claim 1, in the amino acid sequence of AGXT2 shown in SEQ ID NO: 1, at least one selected from the group consisting of T79M and E366Q missense mutation; In the amino acid sequence of ATG2A shown in SEQ ID NO: 2, at least one of the missense mutation selected from the group consisting of R553Q, C1270Y, F472S, R559C; In the amino acid sequence of ATP13A5 shown in SEQ ID NO: 3, at least one missense mutation selected from the group consisting of P389L, A34V, S1041I, T686I, R27Q, and L144M; In the amino acid sequence of CD207 shown in SEQ ID NO: 4, at least one selected from the group consisting of D269G is a missense mutation; * In the nonsense mutation indicates that the amino acid synthesis at the corresponding amino acid position has been completed (the description is omitted below); R321 * at least one nonsense mutation; In the amino acid sequence of COL21A1 as shown in SEQ ID NO: 5, at least one missense mutation selected from the group consisting of A224S, T323S, T651I, and G707V; In the amino acid sequence of CPXM1 shown in SEQ ID NO: 6, at least one selected from the group consisting of R662H and L726P missense mutation; In the amino acid sequence of CS represented by SEQ ID NO: 7, a missense mutation that is at least one of K34R and L389V, and a nonsense mutation that is at least one of R356 *;
In the amino acid sequence of CTSE represented by SEQ ID NO: 8, at least one selected from the group consisting of T116M and P30L, a missense mutation; In the amino acid sequence of FCRL1 shown in SEQ ID NO: 9, at least one of the missense mutations selected from the group consisting of A74T, A284S, and A320V; In the amino acid sequence of LINGO1 shown in SEQ ID NO: 10, at least one missense mutation selected from the group consisting of F410I, A9V, V138I and P549H; In the amino acid sequence of MYH11 shown in SEQ ID NO: 11, at least one of the missense mutations selected from the group consisting of A815T, E1888K, T975M, A732V, A1259V and A334V, and R1609 * at least one nonsense mutation; In the amino acid sequence of PLIN3 shown in SEQ ID NO: 12, the notation of the frame shift mutation is amino acid type (amino acid position) amino acid type fs * (number of nucleotides from amino acid position to stop codon in the downstream direction). (Frame shift insertion mutation, frame shift deletion mutation are all the same notation method, and description will be omitted below.) At least one of frame shift delete (FS del) mutation of Q263Rfs * 14 and Q174Lfs * 48, among A119V At least one missense mutation; In the amino acid sequence of POLR2B shown in SEQ ID NO: 13, at least one missense mutation selected from the group consisting of D45Y, R157W and Q948R; In the amino acid sequence of SERINC3 shown in SEQ ID NO: 14, at least one selected from the group consisting of I45S and D88V is a missense mutation; A kit for prognostic diagnosis of prostate cancer comprising a primer set for prognostic diagnosis of prostate cancer selected from a missense mutation, at least one selected from the group consisting of V193M and V61M, in the amino acid sequence of SLC38A8 shown in SEQ ID NO: 15 .
The method according to claim 5, wherein the AGXT2, ATG2A, ATP13A5, CD207, COL21A1, CPXM1, CS, CTSE, FCRL1, LINGO1, MYH11, PLIN3, POLR2B, SERINC, and mutations in at least one gene selected from the gene group consisting of SLC38A8 If it is confirmed, a method of providing information necessary for prognostic diagnosis of prostate cancer further comprising; determining that the recurrence rate of prostate cancer in the subject is high.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020200026257A KR20200031088A (en) | 2020-03-03 | 2020-03-03 | Gene mutations biomarker that predicts recurrence for prostate cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020200026257A KR20200031088A (en) | 2020-03-03 | 2020-03-03 | Gene mutations biomarker that predicts recurrence for prostate cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20200031088A true KR20200031088A (en) | 2020-03-23 |
Family
ID=69998510
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020200026257A KR20200031088A (en) | 2020-03-03 | 2020-03-03 | Gene mutations biomarker that predicts recurrence for prostate cancer |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20200031088A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022014991A1 (en) * | 2020-07-13 | 2022-01-20 | 가톨릭대학교 산학협력단 | Pathological grade-specific marker for making prognosis of and determining treatment strategy for prostate cancer patient |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101895423B1 (en) | 2016-07-29 | 2018-09-06 | 가천대학교 산학협력단 | The diagnosis bio-marker predicting prostate cancer metastasis and the therapeutic composition suppressing metastasis of castration-resistant prostate cancer |
-
2020
- 2020-03-03 KR KR1020200026257A patent/KR20200031088A/en not_active Application Discontinuation
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101895423B1 (en) | 2016-07-29 | 2018-09-06 | 가천대학교 산학협력단 | The diagnosis bio-marker predicting prostate cancer metastasis and the therapeutic composition suppressing metastasis of castration-resistant prostate cancer |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022014991A1 (en) * | 2020-07-13 | 2022-01-20 | 가톨릭대학교 산학협력단 | Pathological grade-specific marker for making prognosis of and determining treatment strategy for prostate cancer patient |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8007995B2 (en) | Moesin, caveolin 1 and yes associated protein 1 as predictive markers of response to dasatinib in breast cancers | |
| Min et al. | S100A4 expression is associated with lymph node metastasis in papillary microcarcinoma of the thyroid | |
| KR101566368B1 (en) | Urine gene expression ratios for detection of cancer | |
| KR101557183B1 (en) | Prognostic Marker for Diagnosis of Bladder Cancer | |
| US20220229060A1 (en) | Gender-specific markers for diagnosing prognosis and determining treatment strategy for renal cancer patients | |
| US10233502B2 (en) | Compositions for and methods of detecting, diagnosing, and prognosing thymic cancer | |
| US20200232039A1 (en) | Adm2 gene marker for diagnosis or prognosis prediction of thyroid cancer and uses thereof | |
| CN113774140A (en) | Product for predicting sensitivity of colorectal cancer to oxaliplatin treatment | |
| KR20200031088A (en) | Gene mutations biomarker that predicts recurrence for prostate cancer | |
| KR20200025968A (en) | Gender-specific biomarker for the diagnosis and treatment strategy of lung adenocarcinoma | |
| KR20210133200A (en) | Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Gender | |
| KR20200104106A (en) | Recurrence-specific markers for determining treatment strategies and diagnosing prognosis of patient of clear cell renal cell carcinoma | |
| KR20210101179A (en) | Gender-specific markers for diagnosing prognosis and determining treatment strategies of patient of clear cell renal cell carcinoma | |
| KR20180092908A (en) | Survival and death specific for the determination of prognosis and treatment strategy in patients with lung adenocarcinoma biomarker | |
| KR20210113137A (en) | Composition for Diagnosing Prognosis of Kidney Cancer and Kit Comprising Thereof | |
| CN113817829A (en) | Use of biomarkers for the preparation of a product for predicting the sensitivity of colorectal cancer to treatment with oxaliplatin | |
| KR20220129816A (en) | Diagnostic Biomarker For Prognosis of Diffuse Type Gastric Cancer | |
| KR102084658B1 (en) | Metastasis-specific markers for diagnosing prognosis and determining treatment strategies of patient of clear cell renal cell carcinoma | |
| KR20210040921A (en) | Recurrence-specific markers for determining treatment strategies and diagnosing prognosis of patient of clear cell renal cell carcinoma | |
| KR20200012380A (en) | Recurrence-specific markers for diagnosis and treatment strategies for breast cancer patients | |
| KR102259708B1 (en) | Novel biomarker for predicting drug-responsibility to colon cancer | |
| JP2016154447A (en) | Evaluation method of prognosis of pancreatic cancer | |
| KR20210113140A (en) | Composition And Kit For Diagnosing Prognosis Of Kidney Cancer According To Tumor Type | |
| KR20210090594A (en) | Pathologic stage-specific markers for diagnosing prognosis and determining treatment strategies of patients of clear cell renal cell carcinoma | |
| KR20210125456A (en) | Composition And Kit For Diagnosing Prognosis Of Bladder Cancer According To Metastasis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| E902 | Notification of reason for refusal | ||
| WITB | Written withdrawal of application |