CN108504733A - Tumour Individual Chemotherapy medication guide gene SNP site detection combination object - Google Patents
Tumour Individual Chemotherapy medication guide gene SNP site detection combination object Download PDFInfo
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- CN108504733A CN108504733A CN201711230588.XA CN201711230588A CN108504733A CN 108504733 A CN108504733 A CN 108504733A CN 201711230588 A CN201711230588 A CN 201711230588A CN 108504733 A CN108504733 A CN 108504733A
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- 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
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
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- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
Abstract
The invention discloses tumour Individual Chemotherapy medication guide gene SNP site detection combination objects, and the tumour Individual Chemotherapy medication guide gene SNP site detection combination object includes XL NO：1~XL NO：114 primers.The present invention can not only 46 tumour Individual Chemotherapy medication guide genes of one-time detection, totally 58 SNP sites, and have detection sensitivity high the SNP site of tumour Individual Chemotherapy medication guide gene-correlation, it is high specificity, not easy to pollute, safe, the advantages that detection cycle is short, testing result has preferable accuracy and repeatability, by the whole gene polymorphic information for detecting tumor patient, most scientific chemotherapeutical medicine curative effect and evaluating toxic and side effect are carried out for cancer patient, auxiliary doctor is that patient formulates personalized therapy program.
Description
Technical field
The present invention relates to genetic test, biochemical fields, more particularly to tumour Individual Chemotherapy medication guide gene SNP
Site primer composition.
Background technology
According to statistics, newly hair tumor cases are about 3120000 every year in China, about 8500 daily, per minute to have 6 people's quilts
It is diagnosed as possessing cancer, it is 22% that people, which suffer from cancer probability all one's life,.Currently, lung cancer is that the national malignant tumor death rate is highest,
Secondary is liver cancer, gastric cancer, the cancer of the esophagus and colorectal cancer, and the major cancers that males often occur are lung cancer, liver cancer, gastric cancer, oesophagus
Cancer and colorectal cancer, the major cancers that women population is often found are lung cancer, liver cancer, gastric cancer, breast cancer and colorectal cancer.
Malignant tumour primary treatments have surgical operation, chemotherapy, radiotherapy and molecular targeted agents treatment, surgical operation to be
Refer to method surgically, removal cancerous issue repairs damage, grafting device official rank, and radiotherapy refers to between special radioactive ray
It connects or coup injury cell DNA, chemotherapy refers to inhibiting growth of tumour cell breeding using chemicals, killing tumour cell or rush
Into a kind of therapy of tumor cell differentiation.Currently, between several method, chemotherapy accounts for about in clinical therapy of tumor
70%, especially for the patients with advanced cancer for losing surgical operation therapy meaning, chemotherapy is even more main or even uniquely treats hand
Section.Deepening continuously and develop with the research of human activities environment, pharmacogenomics and oncomolecularbiology, it has been found that
Some tumours occur, spread, shift relevant protein molecular, molecular targeted resist to develop some using them as target spot
Tumour medicine, these drugs are different compared to traditional cell toxicant antineoplastic, it can not only inhibit tumor cell proliferation, and
Toxic side effect is small, and specificity is high, high safety, orally available.
Although various treatment means have cancer certain inhibition, more and more clinical datas are shown,
For the same phase, the patient of same histological type, even if using identical therapeutic scheme, curative effect there is also apparent difference,
Our this species diversity is referred to as individuation difference, and with the completion of the Human Genome Project, people gradually recognize：Same type is swollen
The Cell. Mol difference of tumor may be where the reason of leading to tumour individuation difference, and in recent years, many large sizes are clinical
Data (IPASS, INSFORM etc.) shows that the mutation of the SNP site of certain genes and expression variation can help doctor to examine
The disconnected state of an illness and prediction curative effect, if we can before the treatment be sequenced the SNP site of these special genes of patient, to prominent
Becoming situation to be diagnosed, we can give optimal therapeutic scheme according to diagnostic result, reduce many meaningless treatment times,
Medical expense is reduced, improves and generates quality, extends life cycle.This therapy is exactly the personalized treatment of tumour.
A large amount of clinical research confirmation acts on or is metabolized relevant gene expression dose pair in tumour cell with chemotherapeutics
It is to select the necessary foundation of chemotherapeutics that, which there are important influence, the detection of related gene expression level in the effect of chemotherapy, is to ensure that
The important guarantee of Individual Chemotherapy expected effect.NCCN non-small cell clinical therapeutic guidelines are pointed out：" advance receiving platinum-based chemotherapy
The detection of row ERCC1mRNA expressions is remarkably improved treated effect and the survival rate of patient, Patients with Non-small-cell Lung
The effect of expression of RRM1 and gemcitabine, is closely related, and the inspection of RRM1 gene expression doses should be carried out before gemcitabine medication
It surveys." medical college of Hong Kong Chinese University Tony professors Mok initiate IPASS research, compare Gefitinib list medicine and carboplatin+purple
The effect of double medicine chemotherapy of China fir alcohol are as NSCLC first-line treatments difference, the results show that compared with carboplatin+Paclitaxel Chemotherapy, than carrying
In the patient of EGFR mutation, Gefitinib makes its death risk lower 52% (P<0.001), efficient is 71.2%；However, right
Mortality risk (HR=2.85, P are then increased in the treatment of the patient of EGFR wild types, Gefitinib<0.001), it is efficient only
It is 1.1%, so the detection of the gene expression dose of EGFR should be carried out before using Gefitinib.
Use for other chemotherapeutics, also should be according to corresponding gene expression dose depending on, such as BRCA1 and
BRCA2 genes participate in the assembly of DNA recombinase Rad51 subnucleus, and BRCA1 can make the cell after cisplatin treated continue to survive.Therefore,
The low tumor patient of BRCA1 gene expression doses is more suitable for the chemotherapy based on cis-platinum；XRCC1 participates in the base of DNA damage
Reparation approach is cut off, DNA damage repair process caused by cis-platinum or carboplatin is participated in.Therefore the high trouble of XRCC1 gene expression doses
Person is significantly increased using the chemotherapy effect of cis-platinum or carboplatin.It is found also by clinical research, TYMS and DPD expressions are low
Tumor patient receive that cyanogen class chemotherapy effect is preferable, and the low tumor patient of STMN1 expressions receives Vinorelbine treatment
Effect it is preferable, the high tumor patient of TOP2A expressions using Etoposide effect it is preferable.
Because of the gene-correlation of tumour medication and everyone, the detection of tumour Individual Chemotherapy medication gene SNP site
It is significant to each tumor patient with diagnosing.By detect tumor patient whole gene polymorphic information, be cancer patient into
Row most scientific chemotherapeutical medicine curative effect and evaluating toxic and side effect, auxiliary doctor are that patient formulates personalized therapy program.It gives and suffers from
The most suitable therapeutic scheme of person.
Currently, be widely used in tumour Individual Chemotherapy medication guide gene SNP site detection method mainly have it is following several
Kind：Limitation small fragment length polymorphism analysis method (RFLP methods) is used to detect the gene of restriction enzyme site change, can directly judge
Genotype, but cannot be used for not generating the genetic test of new restriction enzyme site, and also RFLP experimental implementations are cumbersome, detection cycle
Long, of high cost, false positive is high, it is difficult to meet clinical detection requirement.Fluorescent quantitative PCR technique, although its sensitivity is high, specificity
Height, the degree of automation is strong, but can there is a situation where that sample pollution, false positive are high, and can only survey a kind of gene type every time.
DNA generation PCR sequencing PCRs, sensitivity is low, can only survey a gene every time, it is difficult to detect low frequency mutational site and false negative rate is high, survey
Sample size needed for sequence is big, and the sequencing period is long, of high cost, complicated for operation, therefore this method is not suitable for clinical detection.
Therefore, how to provide that one kind can relatively convenient be quick, the sequencing period is short, with strong points, testing result accurately may be used
The detection means leaned on becomes industry problem to be solved.
Invention content
In view of the shortcomings of the prior art, the object of the present invention is to provide tumour Individual Chemotherapy medication guide gene SNP positions
Point detection combination object, detection sensitivity is high, high specificity；One-time detection can cover 46 genes, totally 58 SNP sites.
To achieve the goals above, the present invention provides tumour Individual Chemotherapy medication guide gene SNP site detection groups
Object is closed, tumour Individual Chemotherapy medication guide gene SNP site detection combination object includes XL NO:1~XL NO:114 draw
Object；
The XL NO:1~XL NO:114 primer sequences are shown in Table 1.
The present invention detects the high feature of flux height, high sensitivity, specificity, and sensitivity can reach 1%, the DNA of sample
Concentration can be down to 0.1~1ng/ μ l.
According to another specific implementation mode of the present invention, tumour Individual Chemotherapy medication guide gene SNP site detection combination
The group of object becomes：8 μ l of Master Mix, adapter-primer NS-TopGene-PEA and including XL NO:1~XL NO:114 primers
Primer panel；XL NO in primer panel:1~XL NO:A concentration of 100nM of 114 primers.
According to another specific implementation mode of the present invention, the group of Master Mix becomes：PCR buffer(5x)5ul、MgCl2
2 μ l, Taq enzyme 1.5 μ l and ddH2O 8.5μl。
According to another specific implementation mode of the present invention, adapter-primer NS-TopGene-PEA includes NS-TopGene-PEA
1.0：TACACTCTTTCCCTACACGACGCTCTTCCGATCT and NS-TopGene-PEA 1.1：
GATCGGAAGAGCACACGTCTGAACTCCAGTCAC。
According to another specific implementation mode of the present invention, tumour Individual Chemotherapy medication guide gene SNP site detection combination
PCR (PCR) reaction condition of object includes：
Warm-up phase：92~97 DEG C of pre- thermal denaturations 3~10 minutes；
The amplification stage：92~97 DEG C of denaturation 10~20s, 58~65 DEG C of annealing 10~30s, 70~75 DEG C of 10~20s of extension,
And carry out 10~20 cycles.
After DNA sample to be measured is expanded using multiplex PCR enzyme, structure library carries out on a large scale together with upper machine quality-control product
Parallel sequencing (sequencing of two generations), instrument obtain result through data processing and bioinformatic analysis, obtain in sample and contain
The information of SNP site optimal medication is provided for doctor then by large-scale pharmacogenomic data library and big data algorithm
Scheme refers to.
DNA sample to be measured is human genome DNA.
Multiplex PCR process is carried out at the same time negative control experiment, and negative sample used is normal human gene group DNA.
DNA sample to be measured is mankind's cell DNA, tumor tissues genomic DNA, peripheral blood cells DNA or saliva DNA.
The present invention detect gene be 46 tumour Individual Chemotherapy medication guide genes, including ERCC1, RRM1, XRCC1,
The genes such as TYMS and DPD include the important SNP site closely related with tumour medication.
The so-called tumour Individual Chemotherapy medication guide gene of the present invention include 46 genes with the close phase of tumour medication
The important SNP site closed comprising the introne gene chr10 of ABCC2 genes and DNMBP genes gap：101620771
(rs12762549), ERCC1 genes chr19：The important SNP sites (being shown in Table 2) of 45923653 (rs11615) etc. 58.
XL NO in the present composition:1~XL NO:114 primers are referred to for each tumour Individual Chemotherapy medication
One section of sequence near the important SNP site of each of gene is led to be designed.By the design and screening and primer of software through excellent
After changing modification, the degree of skewed popularity amplification reduces, and interfering with each other property is small between each primer, high specificity, expanding effect number.These
Primer is dissolved in test tube as a mixture, is added simultaneously in an experiment.
Upper machine template set-up procedure includes library template dilution, mixing, denaturation, bridge-type PCR amplification and sequencing, the process
Middle reagent composition includes 2N NaOH, free Dntp, sequencing primer and polymerase with fluorescent decoration etc..
Upper machine sequencing reaction process includes 500 sequencing reaction processes of Nextseq cn, and principle is by reversible block
Be sequenced in synthesis and detect the fluorescence signal of building-up process nucleotide with CDD array acquisitions optical signalling, measured with this
The base sequence of DNA
Template library construction process includes target template amplification and the amplification of 500 common templates of Nextseq cn, the reaction
System includes 0.2-1U amplifications Taq enzyme, 10~20 μM of sequence measuring joints universal primers, 1-10xBuffer and 0.2-
1.8xAmpure purifies the reagents such as magnetic bead.
Test data handles the conversion that analysis includes sequencing data, splicing, comparison, Quality Control, the screening of false positive site and dashes forward
Become the processes such as Locus Analysis in Shoots, passes through the final information for obtaining detection sample SNP site of the processing of data.
XL NO:1~XL NO:114 primer sequences are as shown in table 1.
1 tumour Individual Chemotherapy medication guide gene SNP site detection primer sequence of table
The relevant SNP site gene of tumour Individual Chemotherapy medication guide is detected, the present invention susceptible SNP site to be detected is such as
Under：
The 2 relevant SNP site gene of tumour Individual Chemotherapy medication guide of table：
Compared with prior art, the present invention has following advantageous effect：
1, high specificity：For the special SNP design primers of specific gene, positioning captures specific SNP site attachment
Base sequence, specificity are extremely strong.
2, highly practical：For 46 genes 58 SNP sites all with clinically relevant, the medication for cancer patient
There is directive significance, doctor can be helped to provide most suitable therapeutic scheme for cancer patient.
3, testing result directly reflects the expression conditions of SNP site, very precisely.
4, high sensitivity：Detection sensitivity reaches 0.01%, can detect all low frequency mutational sites.
5, easy to operate efficient：Primer is in mixture, and mixture is placed in a test tube；PCR processes are directly added into,
Do not needed multioperation, it is only necessary to it can obtain a result within one day, ultrahigh in efficiency.
6, safety：Whole system does not include poisonous and harmful substance, all non-hazardous to experimenter and environment.
Comprehensive of the present invention has tumour Individual Chemotherapy medication guide gene the susceptible SNP of correlation of Clinical significance of detecting
Site, sequence and experiment reaction system to each primer optimize, and show the powerful advantages of detectability；Not only make inspection
Survey is simple and efficient, and is also had with higher accuracy, high specificity, assay reproducibility and practicability.To swollen
The susceptible SNP site of tumor Individual Chemotherapy medication guide medication gene-correlation has detection sensitivity high, and high specificity is not easy dirt
Dye, safe advantage, testing result have preferable accuracy and repeatability, to needing the cancer patient of chemotherapy to have weight
The meaning wanted can assist doctor to fully understand the expression of patient tumors Individual Chemotherapy medication guide gene, and give suitable
The suggestion of conjunction designs most suitable therapeutic scheme for tumor patient.
The present invention is described in further detail below in conjunction with the accompanying drawings.
Description of the drawings
Fig. 1 a are a segmentation interception figures of the segment distribution map after the completion of library construction in embodiment 1；
Fig. 1 b are another segmentation interception figures of the segment distribution map after the completion of library construction in embodiment 1；
Fig. 2 is the individual instructions therapeutic regimen that analysis assessment obtains in embodiment 1.
Specific implementation mode
Embodiment 1
Tumour Individual Chemotherapy medication guide gene SNP site detection combination object is present embodiments provided, tumour is used for
The detection of chemotherapy of patients medication gene mutation site and guides medication.
One, experiment material
1. a clinical blood sample involved in experiment comes from the 4th hospital of Hebei Medical University.After sample collection, put immediately
Enter and is preserved in -80 degree refrigerators.
2. all primer purity should reach electrophoresis grade (PAGE) or HPLC grades, miscellaneous band is free of.There is provided what combination mechanism was provided
The quality inspection of synthetic product proves, as PAGE electrophoresis results or HPLC analyze collection of illustrative plates, it was demonstrated that answered after purification using PAGE or HPLC
There are apparent unimodal PAGE or HPLC purifying collection of illustrative plates, a concentration of 10ng/ μ l spare.
3. all reagents are bought from regular producer：Multiplex PCR enzyme (KAPA companies), Ampure magnetic beads
Flux, library quantification kit in (BeckmanCoulter companies), Bei Rui and health sequencing reaction universal kit (300 cycle)
(kapa companies).
Two, key instrument
Bei Rui and health NextSeq cn500 sequenators, Stepone plus fluorescence quantitative PCR instruments, Qubi t3.0 fluorescence are fixed
Measure instrument, supercentrifuge, water-bath, whirlpool concussion instrument, refrigerator, baking oven, autoclave.
Three, experimental design
Patients with lung cancer personalization tumour chemotherapy medicament sensitive SNP site is detected, determines the prominent of SNP site according to testing result
Become type.
Four, reaction system and program
1. according to the existing experiment basis in laboratory and empirical studies, and with reference to the operation of NextSeq cn500 examination with computer
Regulation and multiplexed PCR amplification requirement, the multiple reaction system of formulation are as follows：11 μ l of Master Mix, include XL NO:1~XL
NO:8 μ l of primer panel, the 4 μ l of testing gene of 114 primers.
Mas ter Mix groups become：PCR buffer(5x)5μl、MgCl22 μ l, 1.5 μ l of Taq enzyme, ddH2O 4.5μl。
2. carrying out multiplexed PCR amplification response procedures according to the above reaction system：
Warm-up phase：95 DEG C of pre- thermal denaturations 3 minutes；
The amplification stage：95 DEG C of denaturation 15s, 60 DEG C of annealing 30s, 72 DEG C of extension 20s, and carry out 13 cycles.
After the completion of experiment, data process＆analysis is carried out to experimental result.
3. carrying out library construction and examination with computer after the completion of multiple reaction, template library construction process is NextSeq
Cn500 carries out the second wheel template amplification and purifying using universal primer, includes 0.2-1U amplifications Taq in the reaction system
The reagents such as enzyme, 10~20 μM of sequence measuring joints universal primers, 1-10xBuffer and 0.2-1.8xAmpure purifying magnetic beads.Library structure
Building the Ampure magnetic bead dosages used in the process is：2 purifying carry out segment screening after first round template amplification, are for the first time 15
μ l, second is 18 μ l.Magnetic beads for purifying after second wheel template amplification is primary purifying, and dosage is 24 μ l.
Second wheel PCR the specific steps are：
1, first round PCR product 18 μ l of product after purification are added in system, amplification Taq enzyme mixture 10 μ l are general
Primer 2 μ l carry out PCR amplification.
Response procedures are the pre- thermal denaturations of 95-98 DEG C of 30s-3min；95-98 DEG C of 10-15s, 60-65 DEG C of 20-40s, 68-72 DEG C
20-45s recycles 8-12 amplification；68-72 DEG C of 5-1mins, 4 DEG C of preservations.
2, it is purified after expanding：24 μ l Ampure magnetic beads are added in amplified production to be adsorbed, 80% ethyl alcohol is washed to dry in the air afterwards twice
It is dry to be dissolved in water.
In Fig. 1 a and Fig. 1 b, abscissa represents the length of segment, and ordinate represents the concentration (content) of segment.According to experiment
The setting of scheme, after primer panel multiplex amplifications and library construction, purpose product should be 250-500bp or so；Fig. 1 a and
It is shown by Fig. 1 b the result shows that, actual product is consistent with the target of experimental design.
Table 3 is sample examination with computer data analysis table, is by data analyses such as sequence shearing, splicing and Locus Analysis in Shoots
Processing, and the preliminary mutational site profile obtained, can show that the hot spot SNP on tumor susceptibility gene is prominent through data analysis
Become situation.
Table 3 includes following information：Gene name refers to the gene being detected where site, and rs numbers are the websites NCBI SNP numbers
According to library Unified number, mutation type refer to this SNP site mutation the case where, chromosome refer to be detected site where dyeing
Body position, initial position refer to the initial position being detected on the designation of chromosome of site.
Hot spot SNP mutation situation on 3 tumor susceptibility gene of table：
| Gene name | Rs is numbered | Mutation type | Chromosome | Initial position |
| MTHFR | rs1801133 | CC>TC | chr1 | 11856378 |
| FDPS | rs2297480 | TT>GT | chr1 | 155279482 |
| CYP2C8 | rs1934951 | CC>AG | chr10 | 96798548 |
| SLIT1 | rs2784917 | AA>CC | chr10 | 98928942 |
| CASP7 | rs7921977 | CC>TC | chr10 | 115439569 |
| GSTP1 | rs1695 | AA>GA | chr11 | 67352689 |
| RRM1 | rs9937 | AA>CT | chr11 | 4159457 |
| CYP19A1 | rs4646 | AA>CA | chr15 | 51502844 |
| TP53 | rs1042522 | CC>GC | chr17 | 7579472 |
| ERCC1 | rs11615 | TT>CC | chr19 | 45923653 |
| XRCC1 | rs1799782 | CC>TC | chr19 | 44057574 |
| ERCC1 | rs3212986 | CC>TG | chr19 | 45912736 |
| ATIC | rs4673993 | TT>CT | chr2 | 216212339 |
| UGT1A1*28 | rs8175347 | TT>TA7/TA7 | chr2 | 234668881 |
| GALNT14 | rs9679162 | GG>AC | chr2 | 31247514 |
| CBR3 | rs1056892 | GG>TT | chr21 | 37518706 |
| CYP2D6*10 | rs1065852 | GG>AG | chr22 | 42526694 |
| XPC | rs2228001 | CC>AA | chr3 | 14187449 |
| ABCB1 | rs1045642 | TT>CT | chr7 | 87138645 |
| ABCB1 | rs2032582 | TT>GT | chr7 | 87160618 |
| CYP3A4 | rs2740574 | GG>AA | chr7 | 99382096 |
| CYP3A5 | rs776746 | GG>AG | chr7 | 99270539 |
| C8orf34 | rs1517114 | CC>GG | chr8 | 69389217 |
Five, experimental result and analysis
After experiment terminates, the sequencing data of acquisition is analyzed, according to software analysis as a result, detecting and referring to
Sites different genome hg19.By comparing the primer panel and site information of design, detect that tumour personalized chemotherapeutic is easy
Sensillary base carries out human interpretation because of upper SNP site catastrophe, then to catastrophe, and most scientific chemotherapeutic is carried out for cancer patient
Object curative effect and evaluating toxic and side effect, auxiliary doctor are that patient formulates personalized therapy program.
Reference gene group hg19 is the mankind (Homo sapiens) canonical reference genome (GRCh37/hg19), is international
It is general as screening target sequence mutational site or SNP site reference gene sequence, NCBI GenBank
assemblyaccession：GCA_000001405.1.
According to the pattern detection situation of collection, normal SNP site, 46 tumour individual instructions of this example patient are removed
In 58 susceptible SNP sites of medication gene, there are 23 sites to be mutated；This 23 mutational sites are manually solved
It reads, and makes medication guide.
Fig. 2 is Systematic Analysis to be carried out to each site mutation situation, by human interpretation with the important text such as NCCN guides
It offers to instruct, after most scientific chemotherapeutical medicine curative effect and evaluating toxic and side effect are carried out to cancer patient, the personalization formulated refers to
Lead therapeutic regimen general view.
As shown in Fig. 2, fluorouracil is recommended first in column in testing result, Irinotecan shows that toxic side effect is low,
Remaining to have all fallen in alternative, then doctor carries out medication according to report.After fluorouracil chemotherapy 15 days, attending physician is anti-
It is pretty good to present effect, patient lungs' tumour is 5.6*6.1cm by 5.8*6.2cm size reductions, this apparent expression present invention can
To carry out the medication guide of chemotherapeutics to tumor patient well, auxiliary doctor is that patient formulates personalized therapy program.It gives
Give the most suitable therapeutic scheme of patient.
The primer skewed popularity amplification degree of the present invention is low, and interfering with each other property is small between each primer, high specificity, expanding effect
It is good, have detection sensitivity high 58 SNP sites of 46 chemotherapy of tumors direction of medication usage genes, high specificity is not easy to pollute,
Safe advantage.Testing result has good accuracy and repeatability, to needing the tumor patient of progress chemotherapy, especially
It is to have certain auxiliary diagnosis and the meaning of direction of medication usage for losing the patients with advanced cancer of surgical operation therapy meaning.
Although the present invention is disclosed above with preferred embodiment, it is not limited to the range that the present invention is implemented.Any
The those of ordinary skill in field improves in the invention scope for not departing from the present invention when can make a little, i.e., every according to this hair
Bright done same improvement, should be the scope of the present invention and is covered.
Sequence table
<110>Zhong Shantuopu Gene Tech. Company Limited
<120>Tumour Individual Chemotherapy medication guide gene SNP site detection combination object
<130> G266022.17CN
<141> 2017-11-29
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<400> 20
gtgttcctct ccttctcttc ttcc 24
<210> 21
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 21
atccccagtg actgtgtgtt gat 23
<210> 22
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 22
acaagaagcc cctttctttg ttc 23
<210> 23
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 23
cagatgagaa agaggaggaa gaaa 24
<210> 24
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 24
ggaggaaaga attcaaacat ctca 24
<210> 25
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 25
ccaggtgttt caattgcttg atag 24
<210> 26
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 26
caattattgc aaggtttcag gaca 24
<210> 27
<211> 20
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 27
gagatggtca gtctgctgcc 20
<210> 28
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 28
ggccattact ctgaagatgg agat 24
<210> 29
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 29
accgactatt tctccctcaa actc 24
<210> 30
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 30
tcacatacaa atcatccatc cttg 24
<210> 31
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 31
ctggaagttt aggtcaaaga ggct 24
<210> 32
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 32
tgtgctttct gtatcctcag agtg 24
<210> 33
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 33
gtaggttttc tgggaaggga cag 23
<210> 34
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 34
ctgctctttt cacccatcta cagt 24
<210> 35
<211> 18
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 35
gttctgtgcc acacccgt 18
<210> 36
<211> 18
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 36
gacggaggca ggcgaagt 18
<210> 37
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 37
tcaaatctga gggagctgag taac 24
<210> 38
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 38
caaaccagaa tacagcacat gttt 24
<210> 39
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 39
agtctgactc ccctccagat tc 22
<210> 40
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 40
acctaactgg catcttcact tctg 24
<210> 41
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 41
cacgagtcta ggtctcaacc ctac 24
<210> 42
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 42
gcagcccacc tataatactg acct 24
<210> 43
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 43
aagaagagga agaagcagag tcag 24
<210> 44
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 44
ggcaccttca gctttcttta gttc 24
<210> 45
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 45
aacagtccag aacactggga cat 23
<210> 46
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 46
tggttatcaa gggtcatccc tatt 24
<210> 47
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 47
ctacttgatt gatggggctc ac 22
<210> 48
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 48
atatggttgt ccatggtctg gtt 23
<210> 49
<211> 27
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 49
tcgtttttat caattggatc tagacat 27
<210> 50
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 50
atccatgttt aggaagcagt tttg 24
<210> 51
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 51
cactccagca tcactcactt tg 22
<210> 52
<211> 20
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 52
aattcctctt cccctgcctt 20
<210> 53
<211> 21
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 53
cctcacctgg atgggaaaga t 21
<210> 54
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 54
cctctcctga ctgtcatccc tatt 24
<210> 55
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 55
ggtgattagt tgggtctcag tcac 24
<210> 56
<211> 20
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 56
catagggagg gggcactaag 20
<210> 57
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 57
tttcaaatta ttgtttcatt gctg 24
<210> 58
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 58
aagatggcaa aatgctgaaa gtt 23
<210> 59
<211> 21
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 59
ctgaagcctg agtgtgtcca g 21
<210> 60
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 60
cttcctgtac atcttcctct gacc 24
<210> 61
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 61
taccactgga ctctgctctc ttct 24
<210> 62
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 62
tgtgtaagga agatgttggc taaa 24
<210> 63
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 63
taattccagc aggattctta cctg 24
<210> 64
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 64
gagcttgcta agtaattcag tggc 24
<210> 65
<211> 25
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 65
aaataaacat tcaccaactt atgcc 25
<210> 66
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 66
aaatgtttcc cccagaatca tc 22
<210> 67
<211> 25
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 67
atcaagagag aaagttttgg tgagg 25
<210> 68
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 68
gtttctgcca agcctgaact ac 22
<210> 69
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 69
ctttgcagaa taggcttcag acat 24
<210> 70
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 70
actgaaaatg tactgctcat tgct 24
<210> 71
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 71
gagaagagga aagctgacag gat 23
<210> 72
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 72
accaacattt attaagcagc aagc 24
<210> 73
<211> 21
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 73
aaggcactag cgctccttag a 21
<210> 74
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 74
gtcctgtctg tccttctgaa gtgt 24
<210> 75
<211> 21
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 75
ccttcagtcc ctcctgagct a 21
<210> 76
<211> 18
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 76
ggcagaaggg cacaaagc 18
<210> 77
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 77
gtcgaagcag tatggtgtgt tct 23
<210> 78
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 78
catttggtag tgaggcaggt atg 23
<210> 79
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 79
ctaacaaaat gctggatgga aaa 23
<210> 80
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 80
ctagtagcag gggttgactg gtaa 24
<210> 81
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 81
atctgtgtac ctcttcaggg gttt 24
<210> 82
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 82
gctgatgcga gttcttcata cttt 24
<210> 83
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 83
ctctgaaagt gaactccctg ctac 24
<210> 84
<211> 18
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 84
agcaggccca ggacaagt 18
<210> 85
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 85
gaagatactg ttgatcccag tgga 24
<210> 86
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 86
aaacattatg cccgagacta acaa 24
<210> 87
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 87
ctcctactga acctcacctc ttcc 24
<210> 88
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 88
gagtagaacc atatgccagg gtct 24
<210> 89
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 89
gtgtgtacat tgtccaaaat gctg 24
<210> 90
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 90
acacagattg gtctccttct tttg 24
<210> 91
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 91
ctgcctcagt ttgccttctc ag 22
<210> 92
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 92
ctcaaaaccg agaagatgaa gaaa 24
<210> 93
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 93
tatgctgatc atgatgcttt cagt 24
<210> 94
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 94
atttgcctta aggatgatgt tgtg 24
<210> 95
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 95
tttcagtttc actgttacat gcct 24
<210> 96
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 96
aattcttcaa agcacaaaac ggta 24
<210> 97
<211> 20
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 97
atccacctcc tcctccacag 20
<210> 98
<211> 22
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 98
cttcctcctc cagccctatc at 22
<210> 99
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 99
gtgacgttca ggttgttcac gta 23
<210> 100
<211> 18
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 100
accgggctgt gctttctc 18
<210> 101
<211> 23
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 101
acattaggca gtgactcgat gaa 23
<210> 102
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 102
gcaaagaaat aaagcgactg aatg 24
<210> 103
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 103
tgaaaaagat tgctttgagg aatg 24
<210> 104
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 104
tcttagcaat tgtacccatc attg 24
<210> 105
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 105
tagttgtacg acacacagca acct 24
<210> 106
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 106
aacattatgg agagtggcat agga 24
<210> 107
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 107
ctcaatcaat gttactgggg agtc 24
<210> 108
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 108
ttggaaggat gtgtaggagt cttc 24
<210> 109
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 109
taggaaatgg agtggtacag ggta 24
<210> 110
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 110
tggaattttg gtcatatttt gagg 24
<210> 111
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 111
aaactggctt aaagtctgca gttg 24
<210> 112
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 112
ctgacatggc aacttcctaa attc 24
<210> 113
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 113
agataggcag aaacaaaaca gagg 24
<210> 114
<211> 24
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 114
tttcttgata aagtgattca ggga 24
<210> 115
<211> 34
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 115
tacactcttt ccctacacga cgctcttccg atct 34
<210> 116
<211> 33
<212> DNA
<213>Artificial synthesized (Artificial Sequence)
<400> 116
gatcggaaga gcacacgtct gaactccagt cac 33
Claims (5)
1. tumour Individual Chemotherapy medication guide gene SNP site detection combination object, wherein the tumour Individual Chemotherapy medication
It includes XL NO to instruct gene SNP site detection combination object:1~XL NO:114 primers；
The XL NO:1~XL NO:114 primer sequences are as follows：
2. tumour Individual Chemotherapy medication guide gene SNP site detection combination object as described in claim 1, wherein described
The group of tumour Individual Chemotherapy medication guide gene SNP site detection combination object becomes：8 μ l of Master Mix, adapter-primer
NS-TopGene-PEA and including the XL NO:1~XL NO:The primer panel of 114 primers；Described in the primer panel
XL NO:1~XL NO:A concentration of 100nM of 114 primers.
3. tumour Individual Chemotherapy medication guide gene SNP site detection combination object as claimed in claim 2, wherein described
The group of Master Mix becomes：PCR buffer(5x)5ul、MgCl22 μ l, Taq enzyme 1.5 μ l and ddH2O 8.5μl。
4. tumour Individual Chemotherapy medication guide gene SNP site detection combination object as claimed in claim 3, wherein described
Adapter-primer NS-TopGene-PEA includes NS-TopGene-PEA 1.0：TACACTCTTTCCCTACACGACGCTCTTCCGATC
T and NS-TopGene-PEA 1.1：GATCGGAAGAGCACACGTCTGAACTCCAGTCAC.
5. tumour Individual Chemotherapy medication guide gene SNP site detection combination object as claimed in claim 4, wherein described
PCR (PCR) reaction condition of tumour Individual Chemotherapy medication guide gene SNP site detection combination object includes：
Warm-up phase：92~97 DEG C of pre- thermal denaturations 3~10 minutes；
The amplification stage：92~97 DEG C of 10~20s of denaturation, 58~65 DEG C of 10~30s of annealing, 70~75 DEG C extend 10~20s, go forward side by side
10~20 cycles of row.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711230588.XA CN108504733A (en) | 2017-11-29 | 2017-11-29 | Tumour Individual Chemotherapy medication guide gene SNP site detection combination object |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711230588.XA CN108504733A (en) | 2017-11-29 | 2017-11-29 | Tumour Individual Chemotherapy medication guide gene SNP site detection combination object |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108504733A true CN108504733A (en) | 2018-09-07 |
Family
ID=63375389
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711230588.XA Pending CN108504733A (en) | 2017-11-29 | 2017-11-29 | Tumour Individual Chemotherapy medication guide gene SNP site detection combination object |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108504733A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110714077A (en) * | 2019-08-13 | 2020-01-21 | 上海艾汭得基因科技有限公司 | Primer for simultaneously detecting BRCA1/2 exon sequence and chemotherapy drug site and application |
| CN110734974A (en) * | 2019-08-13 | 2020-01-31 | 上海艾汭得基因科技有限公司 | cancer chemotherapy drug SNP locus combinations and detection primers |
| CN110885887A (en) * | 2018-09-10 | 2020-03-17 | 北京福安华生物科技有限公司 | Artificial simulation nucleic acid molecular beacon and kit for detecting rs1517114 site polymorphism of C8orf34 gene |
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| CN110885887A (en) * | 2018-09-10 | 2020-03-17 | 北京福安华生物科技有限公司 | Artificial simulation nucleic acid molecular beacon and kit for detecting rs1517114 site polymorphism of C8orf34 gene |
| CN110885887B (en) * | 2018-09-10 | 2022-04-19 | 北京福安华生物科技有限公司 | Artificial simulation nucleic acid molecular beacon and kit for detecting rs1517114 site polymorphism of C8orf34 gene |
| CN110714077A (en) * | 2019-08-13 | 2020-01-21 | 上海艾汭得基因科技有限公司 | Primer for simultaneously detecting BRCA1/2 exon sequence and chemotherapy drug site and application |
| CN110734974A (en) * | 2019-08-13 | 2020-01-31 | 上海艾汭得基因科技有限公司 | cancer chemotherapy drug SNP locus combinations and detection primers |
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