WO2009126966A2 - Genetic markers indicating biological response to a plk1 kinase inhibitor - Google Patents

Abstract

The invention provides for a method for identifying a cancer patient, such as a breast cancer patient, suitable for treatment with a Polo-like kinase inhibitor, such as GSK461364, comprising detecting modulated expression of PLKl and one or more of a set of predictive biomarkers, or protein encoded thereof.

Description

Genetic Markers Indicating Biological Response to a PLKl Kinase Inhibitor

Inventors: Joe W. Gray, Debopriya Das, Wen-Lin Kuo, Zhi Hu, Nicholas J. Wang,

Heidi S. Feiler, and Paul T. Spellman

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 61/044,437, filed on April 11, 2008, which is hereby incorporated by reference in its entirety.

STATEMENT OF GOVERNMENTAL SUPPORT

[0002] The invention described and claimed herein was made in part under Work for Others Agreement LB06-002417 with GlaxoSmithKline, Inc., under Grant No. U54 CAl 12970 awarded by the National Institutes of Health/National Cancer Institute and under Contract No. DE-AC02-05CH11231 awarded by the U.S. Department of Energy. The Government has certain rights in this invention.

REFERENCE TO SEQUENCE LISTING

[0003] This application hereby incorporates by reference the attached sequence listing in paper and computer readable form, in the .txt file titled, "2566PCT_sequencelisting.txt", created on April 13, 2009.

FIELD OF THE INVENTION

[0004] This invention relates generally to genetic markers involved in the diagnosis and prognosis of cancer, especially breast cancer. This invention also relates to markers predictive for patient response to specific cancer therapeutics.

BACKGROUND OF THE INVENTION

[0005] Breast cancer is one of the most common malignancies among women and shares, together with lung carcinoma, the highest fatality rate of all cancers affecting females. The current treatment of the breast cancer is limited to a very invasive, total or partial mastectomy, radiation therapy, or chemotherapy, the latter two resulting in serious undesirable side effects.

[0006] It is now well established that breast cancers progress through accumulation of genomic and epigenomic aberrations that enable development of aspects of cancer pathophysiology such as reduced apoptosis, unchecked proliferation, increased motility, and increased angiogenesis. Discovery of the genes that contribute to these pathophysiologies when deregulated by recurrent aberrations is important to understanding mechanisms of cancer formation and progression and to guide improvements in cancer diagnosis and treatment.

[0007] Analyses of expression profiles have been particularly powerful in identifying distinctive breast cancer subsets that differ in biological characteristics and clinical outcome. For example, unsupervised hierarchical clustering of microarray derived expression data have identified intrinsically variable gene sets that distinguish five breast cancer subtypes - basal- like, luminal A, luminal B, ERBB2 and normal breast-like. The basal-like and ERBB2 subtypes have been associated with strongly reduced survival durations in patients treated with surgery plus radiation and some studies have suggested that reduced survival duration in poorly performing subtypes is caused by an inherently high propensity to metastasize. These analyses already have led to the development of multi-gene assays that stratify patients into groups that can be offered treatment strategies based on risk of progression. However, the predictive power of these assays is still not as high as desired and the assays have not been fully tested in patient populations treated with aggressive adjuvant chemotherapies.

[0008] Analyses of breast tumors using fluorescence in situ hybridization and comparative genomic hybridization show that breast tumors also display a number of recurrent genome copy number aberrations including regions of high level amplification that have been associated with adverse outcome. This raises the possibility of improved patient stratification through combined analysis of gene expression and genome copy number.

SUMMARY OF THE INVENTION

[0009] The invention provides for a method for identifying a cancer patient suitable for treatment with a Polo-like kinase 1 (PLKl) inhibitor comprising detecting modulated expression of genes selected from the group consisting of: ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15. In one embodiment, the PLKl inhibitor is GSK461364.

[0010] The invention provides for a method for identifying a cancer patient suitable for treatment with a PLKl inhibitor, wherein the patient (a) is PLKl -positive and (b) has an increased or high expression level of ANXAl, TRAPPC4, SYBLl, DDOST, or PHF15. Patients identified as having an increased expression of these genes are predicted to be sensitive to treatment of cancer with a PLKl inhibitor, such as GSK461364. In other embodiments, if the patient is determined to have an increased of high expression level of one or more of the genes encoding SFRSl, EPS8L1, RPL23, SATBl, or INPP4B, are predicted to be resistant to treatment of cancer with a PLKl inhibitor.

[0011] In some embodiments of the invention, an increased or decreased expression level is an expression level of a gene that is more than or less than, respectively, than the expression level of the same gene in a normal tissue or cell sample, such as the cell or tissue sample of non-cancerous cells of the patient or another person that does not have cancer.

[0012] In some embodiments of the invention, an increased or decreased expression level is an expression level of a gene that is more than or less than, respectively, than the average expression level of the same gene in a panel of normal cell lines or cancer cell lines

[0013] In some embodiments of the invention, an increased or decreased expression level is an expression level that is relatively more than or less than, respectively. In some embodiments, a high or low expression level of a gene is a value (a) equal to or (b) higher or lower, respectively, than the average value (Iog₂(expression)) described for the corresponding gene in Table 3.

[0014] The invention provides for a method of treating a cancer patient comprising (a) identifying a cancer patient who is suitable for treatment with a PLKl inhibitor using a method of the present invention, and (b) administering a therapeutically effective amount of the PLKl inhibitor to the patient.

[0015] The invention also provides a computational model useful for identifying a cancer patient suitable for treatment with a PLKl inhibitor, such as GSK461364.

[0016] In some embodiments, the cancer is breast cancer and the cancer patient is a breast cancer patient. In certain embodiments, the breast cancer patient is a PLKl -positive breast cancer patient.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] The foregoing aspects and others will be readily appreciated by the skilled artisan from the following description of illustrative embodiments when read in conjunction with the accompanying drawings.

[0018] Figure IA shows the sensitivity (-log 10(GI₅₀) to GSK461364 for 50 breast cancer cell lines classified as luminal, basal A, basal B or non-malignant human mammary epithelial. The cell lines on the left side of the graph (starting from red arrow pointing down at the GI₅₀ for cell line 184diamond and moving left) are very resistant to GSK461364 with GI50 more than lμM. The basal B type cells are all very sensitive to GSK461364, where the sensitivity status is evaluated using the method of the present invention. Figures IB- ID shows the sensitivity levels of each cell line tested.

[0019] Figure 2 shows breast cancer cell viability measured by CellTiter-Glo® Luminescent Cell Viability Assay of selected cell lines after exposure to GSK461364 for 24h, 48h, and 72h.

[0020] Figure 3 shows the Caspase3 activity detected by Caspase3 GIo Assay after exposure to PLKl inhibitor, GSK461364 for 24h, 48h, and 72h.

[0021] Figure 4 shows that GSK461364 induces cell apoptosis in breast cancer cells. The apoptosis rate was assessed by automatic imaging analysis system with YoPro-1 and H33342 staining after breast cancer cells treated with 1OnM, 5OnM GSK46136 for 24h, 48h and 72h.

[0022] Figure 5 shows GSK461364 induces cell cycle G2/M arrest in sensitive breast cancer cell lines. Cell cycle was analyzed by BrdU and H33342 staining using Cellomics scanner after cells treated with PBS, DMSO and 1OnM GSK461364 for 48h.

[0023] Figure 6 shows network analyses of genes associated with resistance (6A) and sensitive (6B) predictive biomarkers in response to GSK461364 treatment by supervising genomic and mRNA expression signatures of cell lines with the GI₅₀ profile of GSK461364.

[0024] Figure 7 shows pathway analyses of genes associated with sensitive and resistant predictive biomarkers in response to GSK461364 treatment by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK461364.

DETAILED DESCRIPTION

[0025] Before the present invention is described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0026] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0027] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

[0028] It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a gene" includes a plurality of such genes, and so forth.

[0029] These and other objects, advantages, and features of the invention will become apparent to those persons skilled in the art upon reading the details of the invention as more fully described below.

[0030] Polo-like kinase 1 (PLKl), named after the POLO gene of Drosophila melanogaster, is a serine/threonine protein kinase has several important functions throughout the G2->M phase of the cell cycle and is involved in regulating mitotic spindle function in a non-ATP competitive manner. Previous data has shown PLKl to be highly expressed in malignant cells and its expression portends poor prognosis in various human cancers. [0031] Therefore, PIk 1 is a potential oncology drug target, and several small molecules are being developed to target PLKl and are in clinical trials.

[0032] We describe here analyses of molecular responses to GSK461364, a small molecule Polo-like kinase 1 (PLKl) inhibitor with potential antineoplastic activity. Polo-like kinase 1 inhibitor GSK461364 selectively inhibits PIk 1, inducing selective G2/M arrest followed by apoptosis in a variety of tumor cells while causing reversible cell arrest at the Gl and G2 stage without apoptosis in normal cells. GSK461364 is a novel thiophene amide inhibitor of Plkl which has in vitro activity against purified Plkl with a Ki of 2 nM, and >100 fold selectivity versus Plk2 and Plk3. GSK461363 also has excellent in vitro activity (IC50 < 50 nM) in a variety of tumor cell lines. Various compounds and methods of synthesis of GSK461364 are described in the following and are hereby incorporated by reference in their entirety: WO 2004/014899; WO2005/037827; WO2007/030366; WO2007/030361; WO2007/030359; WO2007/143456; and WO2007/143506. With this background, we measured responses to Glaxo SmithKline compound GSK461364 in a panel of 50 breast cell lines at 9 different concentrations between 0.0768nM to 30μM. The GI50 (inhibited growth by 50%) was calculated. Predictive biomarkers of response to GSK461364 treatment were discovered by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK461364. These analyses demonstrated that GSK461364 is more cytotoxic in cell lines representing clinically aggressive basal B breast cancers sub-type than in luminal sub-type cell lines or non-transformed human mammary epithelial cultures. Further validation of these candidate biomarkers is needed. Such predictors could be used to enrich patient populations for potential responders prior to initiating therapy in the clinic and to define tailored therapeutics for individual patients. Thus, because it is contemplated that Plkl is targeted in various human cancers, the present predictive markers can be predictive of prognosis in various human cancers including but not limited to cancers such as breast, ovarian, cervical, gynecological, prostate, colon, pancreatic, squamous cell, small lung cell, lung, epithelial, basal cell, melanoma, sarcomas, carinomas, and gliomas. In one embodiment, the cancer is an epithelial cancer such as breast, ovarian, cervical, prostate, colon, melanoma or pancreatic cancer.

[0033] Individual breast cancers vary in the way they respond to molecularly targeted therapies because they vary in the spectrum of genomic, biological and epigenomic abnormalities accumulated during progression to the malignant state. The panel of 50 breast cancer cell lines has been previously found to mirror the recurrent abnormalities found in primary tumors as well as the variability therein. Therefore, molecular predictors of response to targeted therapies in patients should be the same as those that predict change in growth rate, apoptosis and/or change in cell cycle distribution in cell lines grown in vitro. Thus, while the present Examples show poor and sensitive response indicators to GSK461364 found in a panel of 50 breast cell lines, it is contemplated that these indicators can be used molecular predictors of response to targeted therapies and identifying patients predicted have poor and sensitive response to GSK461364.

[0034] The present Examples and measured responses to GSK461364 are also contemplated to be applicable to other similar compounds that target serine/threonine kinases such as PLKl . in one embodiment, the predictive gene markers should be predictive of sensitivity to other protein kinase inhibitors including amine substituted oxindole compounds and compositions, such as 3-(anilinomethylene) oxindoles as described by Glennon et al. in U.S. Patent No. 6,350,747, hereby incorporated by reference. In another embodiment, the predictive gene markers described herein are predictive of sensitivity to the polo-like kinase inhibitors described in the following and are hereby incorporated by reference in their entirety: WO 2004/014899; WO2005/037827; WO2007/030366; WO2007/030361; WO2007/030359; WO2007/143456; and WO2007/143506.

[0035] The invention provides for a method for identifying a cancer patient suitable for treatment with a polo-like kinase 1 inhibitor, comprising: (a) measuring the expression level of at least one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), wherein an increase in the expression level or a decrease of expression of at least one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 indicates the patient is suitable for treatment with PLKl inhibitor, such as the GSK461364 compound.

[0036] In some embodiments of the invention, the method further comprises (c) measuring the expression level of a gene encoding PLKl in a sample from the patient, and (d) comparing the expression level of the gene encoding PLKl and the expression level of the gene encoding PLKl in the normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), wherein an increase in the expression level of PLKl indicates the patient is suitable for treatment with a PLKl inhibitor, such as the GSK461364 compound.

[0037] In some embodiments of the invention, step (a) comprises measuring the expression level of at least two genes selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient.

[0038] In some embodiments of the invention, step (a) comprises measuring the expression level of at least three genes selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient.

[0039] In some embodiments of the invention, step (a) comprises measuring the expression level of at least four genes selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient.

[0040] In some embodiments of the invention, step (a) comprises measuring the expression levels of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient.

[0041] The expression level of a gene is measured by measuring the amount or number of molecules of mRNA or transcript in a cell. The measuring can comprise directly measuring the mRNA or transcript obtained from a cell, or measuring the cDNA obtained from an mRNA preparation thereof. Such methods of extracting the mRNA or transcript from a cell, or preparing the cDNA thereof are well known to those skilled in the art. In other embodiments, the expression level of a gene can be measured by measuring or detecting the amount of protein or polypeptide expressed, such as measuring the amount of antibody that specifically binds to the protein in a dot blot or Western blot. The proteins described in the present invention can be overexpressed and purified or isolated to homogeneity and antibodies raised that specifically bind to each protein. Such methods are well known to those skilled in the art. [0042] The expression level of a gene is measured from a sample from the patient that comprises essentially a cancer cell or cancer tissue of a cancer tumor. Such methods for obtaining such samples are well known to those skilled in the art. When the cancer is breast cancer, the expression level of a gene is measured from a sample from the patient that comprises essentially a breast cancer cell or breast cancer tissue of a breast cancer tumor.

[0043] The cancer patient is either a patient who is known to be PLKl -positive, that is, overexpresses the PLKl protein, or is not known whether patient is PLKl -positive or not. When the patient is not known whether to be PLKl -positive or not, the PLKl status of the patient is to be determined.

[0044] In some embodiments, the method further comprises measuring the expression level of PLKl of the patients in order to determine whether the patient is an PLKl-positive patient. Methods of assaying for PLKl protein (SEQ ID NO:2) overexpression include methods that utilize immunohistochemistry (IHC) and methods that utilize fluorescence in situ hybridization (FISH). A commercially available IHC test is PathVysion® (Vysis Inc., Downers Grove, 111.). A commercially available FISH test is DAKO HercepTest® (DAKO Corp., Carpinteria, Calif). The expression level of a gene encoding PLKl can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:1 or 3.

[0045] The human homolog of PLKl protein (Drosophila) is SMARCBl, known as Homo sapiens S WI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 (SMARCBl), GenBank Accession No: NM 003073.3 GL55956799 and having the nucleotide sequence and designated as SEQ ID NO: 1 :

1 aacgccagcg cctgcgcact gagggcggcc tggtcgtcgt ctgcggcggc ggcggcggct 61 gaggagcccg gctgaggcgc cagtacccgg cccggtccgc atttcgcctt ccggcttcgg 121 tttccctcgg cccagcacgc cccggccccg ccccagccct cctgatccct cgcagcccgg 181 ctccggccgc ccgcctctgc cgccgcaatg atgatgatgg cgctgagcaa gaccttcggg 241 cagaagcccg tgaagttcca gctggaggac gacggcgagt tctacatgat cggctccgag 301 gtgggaaact acctccgtat gttccgaggt tctctgtaca agagataccc ctcactctgg 361 aggcgactag ccactgtgga agagaggaag aaaatagttg catcgtcaca tgatcacgga 421 tacacgactc tagccaccag tgtgaccctg ttaaaagcct cggaagtgga agagattctg 481 gatggcaacg atgagaagta caaggctgtg tccatcagca cagagccccc cacctacctc 541 agggaacaga aggccaagag gaacagccag tgggtaccca ccctgcccaa cagctcccac 601 cacttagatg ccgtgccatg ctccacaacc atcaacagga accgcatggg ccgagacaag 661 aagagaacct tccccctttg ctttgatgac catgacccag ctgtgatcca tgagaacgca 721 tctcagcccg aggtgctggt ccccatccgg ctggacatgg agatcgatgg gcagaagctg 781 cgagacgcct tcacctggaa catgaatgag aagttgatga cgcctgagat gttttcagaa 841 atcctctgtg acgatctgga tttgaacccg ctgacgtttg tgccagccat cgcctctgcc 901 atcagacagc agatcgagtc ctaccccacg gacagcatcc tggaggacca gtcagaccag 961 cgcgtcatca tcaagctgaa catccatgtg ggaaacattt ccctggtgga ccagtttgag 1021 tgggacatgt cagagaagga gaactcacca gagaagtttg ccctgaagct gtgctcggag 1081 ctggggttgg gcggggagtt tgtcaccacc atcgcataca gcatccgggg acagctgagc

1141 tggcatcaga agacctacgc cttcagcgag aaccctctgc ccacagtgga gattgccatc

1201 cggaacacgg gcgatgcgga ccagtggtgc ccactgctgg agactctgac agacgctgag

1261 atggagaaga agatccgcga ccaggacagg aacacgaggc ggatgaggcg tcttgccaac

1321 acggccccgg cctggtaacc agcccatcag cacacggctc ccacggagca tctcagaaga

1381 ttgggccgcc tctcctccat cttctggcaa ggacagaggc gaggggacag cccagcgcca

1441 tcctgaggat cgggtggggg tggagtgggg gcttccaggt ggcccttccc ggcacacatt

1501 ccatttgttg agccccagtc ctgcccccca ccccaccctc cctacccctc cccagtctct

1561 ggggtcagga agaaacctta ttttaggttg tgttttgttt ttgtatagga gccccaggca

1621 gggctagtaa cagtttttaa ataaaaggca acaggtcatg ttcaatttct tcaacaaaaa

1681 aaaaaaaaaa

[0046] The human homolog of PLKl protein (Drosophila) is SMARCBl, known as Homo sapiens S WI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 (SMARCBl), GenBank Accession No: NM OO 1007468.1 GL55956800 having th following nucleotide sequence and designated as SEQ ID NO:3 : i aacgccagcg cctgcgcact gagggcggcc tggtcgtcgt ctgcggcggc ggcggcggct

61 gaggagcccg gctgaggcgc cagtacccgg cccggtccgc atttcgcctt ccggcttcgg

121 tttccctcgg cccagcacgc cccggccccg ccccagccct cctgatccct cgcagcccgg

181 ctccggccgc ccgcctctgc cgccgcaatg atgatgatgg cgctgagcaa gaccttcggg

241 cagaagcccg tgaagttcca gctggaggac gacggcgagt tctacatgat cggctccgag

301 gtgggaaact acctccgtat gttccgaggt tctctgtaca agagataccc ctcactctgg

361 aggcgactag ccactgtgga agagaggaag aaaatagttg catcgtcaca tgatcacgga

421 tacacgactc tagccaccag tgtgaccctg ttaaaagcct cggaagtgga agagattctg

481 gatggcaacg atgagaagta caaggctgtg tccatcagca cagagccccc cacctacctc

541 agggaacaga aggccaagag gaacagccag tgggtaccca ccctgcccaa cagctcccac

601 cacttagatg ccgtgccatg ctccacaacc atcaacagga accgcatggg ccgagacaag

661 aagagaacct tccccctttg ctttgatgac catgacccag ctgtgatcca tgagaacgca

721 tctcagcccg aggtgctggt ccccatccgg ctggacatgg agatcgatgg gcagaagctg

781 cgagacgcct tcacctggaa catgaatgag aagttgatga cgcctgagat gttttcagaa

841 atcctctgtg acgatctgga tttgaacccg ctgacgtttg tgccagccat cgcctctgcc

901 atcagacagc agatcgagtc ctaccccacg gacagcatcc tggaggacca gtcagaccag

961 cgcgtcatca tcaagctgaa catccatgtg ggaaacattt ccctggtgga ccagtttgag

1021 tgggacatgt cagagaagga gaactcacca gagaagtttg ccctgaagct gtgctcggag

1081 ctggggttgg gcggggagtt tgtcaccacc atcgcataca gcatccgggg acagctgagc

1141 tggcatcaga agacctacgc cttcagcgag aaccctctgc ccacagtgga gattgccatc

1201 cggaacacgg gcgatgcgga ccagtggtgc ccactgctgg agactctgac agacgctgag

1261 atggagaaga agatccgcga ccaggacagg aacacgaggc ggatgaggcg tcttgccaac

1321 acggccccgg cctggtaacc agcccatcag cacacggctc ccacggagca tctcagaaga

1381 ttgggccgcc tctcctccat cttctggcaa ggacagaggc gaggggacag cccagcgcca

1441 tcctgaggat cgggtggggg tggagtgggg gcttccaggt ggcccttccc ggcacacatt

1501 ccatttgttg agccccagtc ctgcccccca ccccaccctc cctacccctc cccagtctct

1561 ggggtcagga agaaacctta ttttaggttg tgttttgttt ttgtatagga gccccaggca

1621 gggctagtaa cagtttttaa ataaaaggca acaggtcatg ttcaatttct tcaacaaaaa

1681 aaaaaaaaaa

[0047] The ANXAl protein (SEQ ID NO: 6) is also known as annexin Al protein, a Ca(2+) dependent phospholipid binding protein with phospholipase A2 inhibitory activity. The expression level of a gene encoding ANXAl can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:5. [0048] The TRAPPC4 protein (SEQ ID NO: 8) is also known as Homo sapiens trafficking protein particle complex 4. The expression level of a gene encoding TRAPPC4 can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:7.

[0049] The SFRSl protein (SEQ ID NO: 10 or 12) is also known as Homo sapiens splicing factor, arginine/serine-rich 1 (splicing factor 2, alternate splicing factor) (SFRSl), transcript variant 1 and transcript variant 2. The expression level of a gene encoding SFRSl can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:9 or 11.

[0050] The EPS8Llprotein (SEQ ID NO: 14 or 16) is also known as Homo sapiens EPS8-like 1 (EPS8L1), having a transcript variant 1 and transcript variant 2, and related to epidermal growth factor receptor pathway substrate 8 (EPS 8), a substrate for the epidermal growth factor receptor. The expression level of a gene encoding EPS8L1 can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO: 13 or 15.

[0051] The RPL23 protein (SEQ ID NO: 18) is also known as Homo sapiens ribosomal protein L23. The expression level of a gene encoding RPL23 can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO: 17.

[0052] The SYBLl protein (SEQ ID NO:20) is also known as synaptobrevin-like 1 protein and as Homo sapiens vesicle-associated membrane protein 7 (VAMP7). The expression level of a gene encoding SYBLl can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO: 19.

[0053] The DDOST protein (SEQ ID NO:22) is also known as Homo sapiens dolichyl- diphosphooligosaccharide-protein glycosyltransferase protein. The expression level of a gene encoding DDOST can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:21.

[0054] The SATBl protein (SEQ ID NO:24) is also known as Homo sapiens SATB homeobox 1 protein or special AT-rich sequence binding protein 1 which binds to nuclear matrix/scaffold-associating DNA' s. The expression level of a gene encoding SATBl can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:23.

[0055] The INPP4B protein (SEQ ID NO:26 and 28) is also known as Homo sapiens inositol polyphosphate -4-phosphatase, type II, 105kDa (INPP4B), transcript variant 1 and transcript variant 2 . The expression level of a gene encoding INPP4B can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:25 or 27.

[0056] The PHF 15 protein (SEQ ID NO: 30) is also known as Homo sapiens PHD (zinc) finger protein 15. The expression level of a gene encoding RPL23 can be measured using an oligonucleotide derived from the nucleotide sequence of SEQ ID NO:29.

[0057] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens annexin Al (ANXAl) protein (SEQ ID NO:5) having GenBank Accession

No: NM 000700:

agtgtgaaat cttcagagaa gaatttctct ttagttcttt gcaagaaggt agagataaag acactttttc aaaaatggca atggtatcag aattcctcaa gcaggcctgg tttattgaaa atgaagagca ggaatatgtt caaactgtga agtcatccaa aggtggtccc ggatcagcgg tgagccccta tcctaccttc aatccatcct cggatgtcgc tgccttgcat aaggccataa tggttaaagg tgtggatgaa gcaaccatca ttgacattct aactaagcga aacaatgcac agcgtcaaca gatcaaagca gcatatctcc aggaaacagg aaagcccctg gatgaaacac ttaagaaagc ccttacaggt caccttgagg aggttgtttt agctctgcta aaaactccag cgcaatttga tgctgatgaa cttcgtgctg ccatgaaggg ccttggaact gatgaagata ctctaattga gattttggca tcaagaacta acaaagaaat cagagacatt aacagggtct acagagagga actgaagaga gatctggcca aagacataac ctcagacaca tctggagatt ttcggaacgc tttgctttct cttgctaagg gtgaccgatc tgaggacttt ggtgtgaatg aagacttggc tgattcagat gccagggcct tgtatgaagc aggagaaagg agaaagggga cagacgtaaa cgtgttcaat accatcctta ccaccagaag ctatccacaa cttcgcagag tgtttcagaa atacaccaag tacagtaagc atgacatgaa caaagttctg gacctggagt tgaaaggtga cattgagaaa tgcctcacag ctatcgtgaa gtgcgccaca agcaaaccag ctttctttgc agagaagctt catcaagcca tgaaaggtgt tggaactcgc cataaggcat tgatcaggat tatggtttcc cgttctgaaa ttgacatgaa tgatatcaaa gcattctatc agaagatgta tggtatctcc ctttgccaag ccatcctgga tgaaaccaaa ggagattatg agaaaatcct ggtggctctt tgtggaggaa actaaacatt cccttgatgg tctcaagcta tgatcagaag actttaatta tatattttca tcctataagc ttaaatagga aagtttcttc aacaggatta cagtgtagct acctacatgc tgaaaaatat agcctttaaa tcatttttat attataactc tgtataatag agataagtcc attttttaaa aatgttttcc ccaaaccata aaaccctata caagttgttc tagtaacaat acatgagaaa gatgtctatg tagctgaaaa taaaatgacg tcacaagac

[0058] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens TRAPPC4 (SEQ ID NO:7) having GenBank Accession No: MM_016146:

tgacgcatac tatagcgctg ttttcctgca ctgataaacg aaaagcaatc caccaggtct cggcagctaa ctttccggca ctacttatgc ccgagcgtgt cgtcccagtg cgcaagtgca gcaggtggct acggaggggc gcgggaggaa gaggaggagg aggaggaggc tgggttgggc cggcgcaagt gctgtgatgc ggttccgggc agggttctgt agaatctgaa taccagtttc cgagcggcaa ggcagcgatg gcgattttta gtgtgtatgt ggtgaacaaa gctggcggct tgatttacca gttggacagc tacgcgccac gggctgaggc tgagaaaact ttcagttatc cgctggatct gctgctcaag ctacacgatg agcgtgtgtt ggttgctttc ggccagcggg acggcatccg agtgggtcat gcagtgctgg ccatcaatgg catggacgtg aatggcaggt acacggccga cgggaaagag gtgctggagt atctgggtaa ccctgctaat tacccggtgt ccattcgatt tggccggccc cgcctcactt ctaatgagaa gcttatgctg gcctccatgt tccactcgct ctttgccatc ggctcccagc tgtctcctga acagggaagc tcaggcattg agatgctgga gacagacaca ttcaaattgc actgctacca gacactgaca gggatcaagt ttgtggttct agcagatcct aggcaagctg gaatagattc tcttctccga aagatttatg agatttactc agactttgcc ctcaagaatc cattctattc cttagaaatg cctatcaggt gtgagctctt tgaccagaac ctgaagctag ctctggaggt ggcagagaag gctggaactt ttggacctgg gtcataggct gaacctgtta tggaccccca aattctgaga gttcctgcaa caagaatact gctgttgaca ctccagtgga aatcccagca gccttgttag tgcacttgaa agtgggagaa tgctgaccct gatgacttgt actgattcct gagccttaac actgtgctct ttccttctgt atataccatg gtcttacttt ccaactctgt acagatttat ttatggagga gctaggtcca taaatgttgt aataaatatt cctttgatct tggtgtttgc gtaaaaaaaa aaaaaaaaaa aaaaaa

[0059] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens (SFRSl), isoform 1 (SEQ ID NO:9) having GenBank Accession No: NM 006924:

gttgcgctcc cgcgcgtgcg tgttgggatc gaatcgctgt ttccttccgc ttctcttcct ctgtctcccc cccatatccg tgcgccgagc tgataaaggc gccattttgg aggggccgcg ggagacgtgg tgccgctgcg ggctcgctct gccgtgcgct aggcttggtg ggaaggcctg ttctcgagtc cgcgcttttc gtcaccgcca tgtcgggagg tggtgtgatt cgtggccccg cagggaacaa cgattgccgc atctacgtgg gtaacttacc tccagacatc cgaaccaagg acattgagga cgtgttctac aaatacggcg ctatccgcga catcgacctc aagaatcgcc gcgggggacc gcccttcgcc ttcgttgagt tcgaggaccc gcgagacgcg gaagacgcgg tgtatggtcg cgacggctat gattacgatg ggtaccgtct gcgggtggag tttcctcgaa gcggccgtgg aacaggccga ggcggcggcg ggggtggagg tggcggagct ccccgaggtc gctatggccc cccatccagg cggtctgaaa acagagtggt tgtctctgga ctgcctccaa gtggaagttg gcaggattta aaggatcaca tgcgtgaagc aggtgatgta tgttatgctg atgtttaccg agatggcact ggtgtcgtgg agtttgtacg gaaagaagat atgacctatg cagttcgaaa actggataac actaagttta gatctcatga gggagaaact gcctacatcc gggttaaagt tgatgggccc agaagtccaa gttatggaag atctcgatct cgaagccgta gtcgtagcag aagccgtagc agaagcaaca gcaggagtcg cagttactcc ccaaggagaa gcagaggatc accacgctat tctccccgtc atagcagatc tcgctctcgt acataagatg attggtgaca ctttttgtag aacccatgtt gtatacagtt ttcctttatt cagtacaatc ttttcatttt ttaattcaaa ctgttttgtt cagaatgggc taaagtgttg aattgcattc ttgtaatatc cccttgctcc taacatctac attcccttcg tgtctttgat aaattgtatt ttaagtgatg tcatagacag gattgtttaa atttagttaa ctccatactc ttcagactgt gatattgtgt aaatgtctat ctgccctggt ttgtgtgaac tgggatgttg ggggtgtttg tggttatctt acctggggaa gttcttatgt ttatcttgct tttcatgtgt ctttctgtag acatatctga agagatggat taagaatgct ttggattaag gattgtggag cacatttcaa tcattttagg attgtcaaaa ggaggattga ggaggatcag atcaataatg gaggcaatgg tatgactcca agtgctattg tcacagatga aattggcagt attgacctta tactaaaagg caggggttaa aaatgattat atacattttc cttaaaacac ttgcaaacat tttattcagt tgtctttagc tacaattgct ttgcttttta aaccttggca attgtggcaa aattatattg cccattttgt agcaacttat tttgctccct tccccccatt tttgttttaa tagggactaa tgtgggaaga actggctaat ttgtcacagt gcttagttac aactgttaat gtgtgacctg ctgttggtgt acatgtgggt acagggtgtt tttaaatcca acaagataga gtataatatc aatactgcta aatctgcatg tcctctgtgt gactgataga gcgttgctat ttcatttttt taagacaaaa tgaaagcaaa atatagagtt ccaatgtatt ggtgtagata atctagttgg gaatactttt aagtctcacc ttccccttta aactaatatt cataattggt tcatatgttt aaaagacttt aatttacaaa ttaaattgca aatgggagca ttagatttag ttttagactt aggtgggtag caatgccagt aaacttaaat tacgtaactt cttgcaacca cgaaacctgt aatacgctgt acagtaacaa gtgttggcat tatcagttga actgtaaata caaaatgctt cttccaatta gtctctatga tgattaagtt tctaaaattt atctgaacac cattcagaaa cttgttttgg ggaatttgat agttattgat gtgcatctgt taaactgatg acagacataa ctcatcattc cccagaaacc ttttttgatt acagtatcta acattttgcc tcctcttttt tggttttgct ggttataaag gtttggattg gagagggctc actggatccc aatccttgga gctggatcat tggattcaaa tcataatgtg gataggatag ggaggatgaa ttaccaggat tcatggagcg ggatcagatt accaggaaca taggagtgga ttcctgcccc aaccaaaccg cattcgtgtg gattttttta ttcaacttaa ttggctattc caaagatttt ttttttccta tttttgacga ttggagccct taagatgcac gatggaattg tgttttgcgt tttttggtaa aaggagcaaa gcgaggacct ggagataaac gctggagcaa tctccttgga aggattcagc acgagtagat ggtaaacatt taaaggggaa agggggggtt tgtttaaaat agtaaatcag taagtcactt ctaaatttaa agaaaacaaa attggagttg aagaataagt aggtttccaa ttggctattg ccgttttctt tgaaaaaata aacatttttt aaaaaactat gcatggttgt cctttttcct cttcatgtaa gattctaact gggtctatca gttaatcttt aaattgttaa gtaagataag attttgactc ttgtgttaat gtgttagcaa attaaaagtt cttaaaaggc aatctaatgg tattagccat cttttattgt taattgtaaa agtcttcagg ggaaagcaaa aggggagaat aaggcatttg tgtatgtaac ttggtaaatg acggtggggg atggatctag catctgaaag ataagcttct ctactttgtt ataaagtggt taaaaaacta tagatgctgc ttattttctg gtggtcatag acaacatagg cttttgtgca aaattggttg atggctacta atgttcactt ggagatagct tttgatattc tcaatgaaac tcatctcaaa aaaaggtaag tattaaatgt taacatcagc acagatgtat tagaactgtt ttttgttttt gagacagagt ctcgctctgt tctccagact ggagggcagt ggtgtgatct aggctcactg caacctccac ccctggattt gagtgattct cgtgcctcag tctcccaagt agctgagact acaagtgtgt gccacccttg cccggctaat tttgtatttt tagtagagat gtggtttctc tgtgttaccc aggctggtcc caaaactcct ggcctcaagt gatctgcctg ccttggcctc ccaaagtgtt aggattacag gtgtgagcca ccatgctcag cctgtagaac ttttaaccca agtctcattt cttttttgaa agggaagagt gcacaagatt aactgcttct ttggatgaat cattgttaat aaaaagctgg gcatttagaa ttttgcctta taagcccttc tccaaccata agattatttt gtaccaaaaa ctttggtgtt ctctaccaaa gcagttaaaa acttttagcc tgctacttct tgtatttgtc tactgacagc cccttggtac tatttaggtt gggggagggg acctaaaata aatagacttt aacatttccc ttgggtgcta atcatagttg gaagttgaat ttaaggtgat tatttgggtg acaattaaaa acctaaggaa aaccagaaat cttggtagtg gaagaaatgt gtaaggtcac cccaatcggt agattttaat gaacgttgtg gaatgttggg aagaggggat gttaagttga atgcagaatt tcactaagta cttagtgtaa gtttaaggat gtagctcttt ttatctaaga attcaatgta atggccaaaa ggcagattta ctgtttaaaa atttgaataa ttttacatga cattcttgaa attctaagaa gttttatgtg tagaacattt taaaaattca tcagattatt aaagggaaaa taaatgatta atgataattt tggaaggtta atgtgagcta gacttaagta aactttggtt catttgtgtt cattgaatgt tttggaaatg accaaaaaat gtaaatggcc ttcactcaag tttgagtgtt taaagttgaa agatgtgctc tactaaaagt tatagtaatt ctaacctcac attgaaatga gacagtattc cttgttatac aggctgaatt tgaagattag agaggatcta atgtttactt aggtaaaggg gcataggttt tgtagttaag atgaccagac agctaaaagc tgtgatggga agtatggact gctcctattt atagtctcag aaaatggacc tttaggtctc tatccgtatt ggcaattatt agaagaaagt tacacccttt tgaaactaca aaagctgtct tggaatttcc ccctcttctc cctatttatg tccccttaga atattttagg gagcctataa ttattttcta accaaggaaa aacttaagtc tctttaagaa gcaattactt ttcataacat cagattgaat aacccacctt gctgttcagc ccacatccta ctggaaacaa aaggtaagaa acccattttc tggttcttga ttgtttgggt ctgaattttg tttttaaaac taagctaagt ttaatgtttt ttaaaatgct gtttggaata tgaatagatt ccccgtaaaa tgatttttcc taagttttat gctttagtaa atattcagtg ctcacgtctg tgcatcatag tgcttgcgtt taatatgatt tattgtagaa tctcaacttt tcttggtgtt tgttgtcttt gaaacattgt cttggtcatt agggctggtg ttttcacatt tctgtggtca aggtggattt cttatgtgtg cctttttgct tactttgtat atgaattttg taatttaaat tgcaagtaag ttatatatat gtatttacca taaatagtat taaaagatga gaaactgtta gactgaagtt ctgttgtaac ataaccatta tttccatcac agtatgaaga ctgcaaacgc agaaaacaga ttacagtctc ttatccattt tttgaaatcc aaaaactacg aaaacaaaag attttctgtt gttgagctaa ttaaatgtga accctgacca gaaaaaaaaa aaaaaaaaaa aaaaaaaa

[0060] The following nucleotide sequence comprises the mRNA transcript encoding Homo sapiens (SFRSl), isoform 2 (SEQ ID NO:11) having GenBank Accession No: NM 1078166:

gttgcgctcc cgcgcgtgcg tgttgggatc gaatcgctgt ttccttccgc ttctcttcct ctgtctcccc cccatatccg tgcgccgagc tgataaaggc gccattttgg aggggccgcg ggagacgtgg tgccgctgcg ggctcgctct gccgtgcgct aggcttggtg ggaaggcctg ttctcgagtc cgcgcttttc gtcaccgcca tgtcgggagg tggtgtgatt cgtggccccg cagggaacaa cgattgccgc atctacgtgg gtaacttacc tccagacatc cgaaccaagg acattgagga cgtgttctac aaatacggcg ctatccgcga catcgacctc aagaatcgcc gcgggggacc gcccttcgcc ttcgttgagt tcgaggaccc gcgagacgcg gaagacgcgg tgtatggtcg cgacggctat gattacgatg ggtaccgtct gcgggtggag tttcctcgaa gcggccgtgg aacaggccga ggcggcggcg ggggtggagg tggcggagct ccccgaggtc gctatggccc cccatccagg cggtctgaaa acagagtggt tgtctctgga ctgcctccaa gtggaagttg gcaggattta aaggatcaca tgcgtgaagc aggtgatgta tgttatgctg atgtttaccg agatggcact ggtgtcgtgg agtttgtacg gaaagaagat atgacctatg cagttcgaaa actggataac actaagttta gatctcatga ggtaggttat acacgtattc ttttctttga ccagaattgg atacagtggt cttaacagtg gaatttcaag gtaaggattc aggcaaggtt gtccaagtaa attgccagat ttctggtttt agttacattg tattcattca gcatgtctga agatagatga aagcttagat ctttcaatgg aaagttctgt ctatccaata gggagaaact gcctacatcc gggttaaagt tgatgggccc agaagtccaa gttatggaag atctcgatct cgaagccgta gtcgtagcag aagccgtagc agaagcaaca gcaggagtcg cagttactcc ccaaggagaa gcagaggatc accacgctat tctccccgtc atagcagatc tcgctctcgt acataagatg attggtgaca ctttttgtag aacccatgtt gtatacagtt ttcctttatt cagtacaatc ttttcatttt ttaattcaaa ctgttttgtt cagaatgggc taaagtgttg aattgcattc ttgtaatatc cccttgctcc taacatctac attcccttcg tgtctttgat aaattgtatt ttaagtgatg tcatagacag gattgtttaa atttagttaa ctccatactc ttcagactgt gatattgtgt aaatgtctat ctgccctggt ttgtgtgaac tgggatgttg ggggtgtttg tggttatctt acctggggaa gttcttatgt ttatcttgct tttcatgtgt ctttctgtag acatatctga agagatggat taagaatgct ttggattaag gattgtggag cacatttcaa tcattttagg attgtcaaaa ggaggattga ggaggatcag atcaataatg gaggcaatgg tatgactcca agtgctattg tcacagatga aattggcagt attgacctta tactaaaagg caggggttaa aaatgattat atacattttc cttaaaacac ttgcaaacat tttattcagt tgtctttagc tacaattgct ttgcttttta aaccttggca attgtggcaa aattatattg cccattttgt agcaacttat tttgctccct tccccccatt tttgttttaa tagggactaa tgtgggaaga actggctaat ttgtcacagt gcttagttac aactgttaat gtgtgacctg ctgttggtgt acatgtgggt acagggtgtt tttaaatcca acaagataga gtataatatc aatactgcta aatctgcatg tcctctgtgt gactgataga gcgttgctat ttcatttttt taagacaaaa tgaaagcaaa atatagagtt ccaatgtatt ggtgtagata atctagttgg gaatactttt aagtctcacc ttccccttta aactaatatt cataattggt tcatatgttt aaaagacttt aatttacaaa ttaaattgca aatgggagca ttagatttag ttttagactt aggtgggtag caatgccagt aaacttaaat tacgtaactt cttgcaacca cgaaacctgt aatacgctgt acagtaacaa gtgttggcat tatcagttga actgtaaata caaaatgctt cttccaatta gtctctatga tgattaagtt tctaaaattt atctgaacac cattcagaaa cttgttttgg ggaatttgat agttattgat gtgcatctgt taaactgatg acagacataa ctcatcattc cccagaaacc ttttttgatt acagtatcta acattttgcc tcctcttttt tggttttgct ggttataaag gtttggattg gagagggctc actggatccc aatccttgga gctggatcat tggattcaaa tcataatgtg gataggatag ggaggatgaa ttaccaggat tcatggagcg ggatcagatt accaggaaca taggagtgga ttcctgcccc aaccaaaccg cattcgtgtg gattttttta ttcaacttaa ttggctattc caaagatttt ttttttccta tttttgacga ttggagccct taagatgcac gatggaattg tgttttgcgt tttttggtaa aaggagcaaa gcgaggacct ggagataaac gctggagcaa tctccttgga aggattcagc acgagtagat ggtaaacatt taaaggggaa agggggggtt tgtttaaaat agtaaatcag taagtcactt ctaaatttaa agaaaacaaa attggagttg aagaataagt aggtttccaa ttggctattg ccgttttctt tgaaaaaata aacatttttt aaaaaactat gcatggttgt cctttttcct cttcatgtaa gattctaact gggtctatca gttaatcttt aaattgttaa gtaagataag attttgactc ttgtgttaat gtgttagcaa attaaaagtt cttaaaaggc aatctaatgg tattagccat cttttattgt taattgtaaa agtcttcagg ggaaagcaaa aggggagaat aaggcatttg tgtatgtaac ttggtaaatg acggtggggg atggatctag catctgaaag ataagcttct ctactttgtt ataaagtggt taaaaaacta tagatgctgc ttattttctg gtggtcatag acaacatagg cttttgtgca aaattggttg atggctacta atgttcactt ggagatagct tttgatattc tcaatgaaac tcatctcaaa aaaaggtaag tattaaatgt taacatcagc acagatgtat tagaactgtt ttttgttttt gagacagagt ctcgctctgt tctccagact ggagggcagt ggtgtgatct aggctcactg caacctccac ccctggattt gagtgattct cgtgcctcag tctcccaagt agctgagact acaagtgtgt gccacccttg cccggctaat tttgtatttt tagtagagat gtggtttctc tgtgttaccc aggctggtcc caaaactcct ggcctcaagt gatctgcctg ccttggcctc ccaaagtgtt aggattacag gtgtgagcca ccatgctcag cctgtagaac ttttaaccca agtctcattt cttttttgaa agggaagagt gcacaagatt aactgcttct ttggatgaat cattgttaat aaaaagctgg gcatttagaa ttttgcctta taagcccttc tccaaccata agattatttt gtaccaaaaa ctttggtgtt ctctaccaaa gcagttaaaa acttttagcc tgctacttct tgtatttgtc tactgacagc cccttggtac tatttaggtt gggggagggg acctaaaata aatagacttt aacatttccc ttgggtgcta atcatagttg gaagttgaat ttaaggtgat tatttgggtg acaattaaaa acctaaggaa aaccagaaat cttggtagtg gaagaaatgt gtaaggtcac cccaatcggt agattttaat gaacgttgtg gaatgttggg aagaggggat gttaagttga atgcagaatt tcactaagta cttagtgtaa gtttaaggat gtagctcttt ttatctaaga attcaatgta atggccaaaa ggcagattta ctgtttaaaa atttgaataa ttttacatga cattcttgaa attctaagaa gttttatgtg tagaacattt taaaaattca tcagattatt aaagggaaaa taaatgatta atgataattt tggaaggtta atgtgagcta gacttaagta aactttggtt catttgtgtt cattgaatgt tttggaaatg accaaaaaat gtaaatggcc ttcactcaag tttgagtgtt taaagttgaa agatgtgctc tactaaaagt tatagtaatt ctaacctcac attgaaatga gacagtattc cttgttatac aggctgaatt tgaagattag agaggatcta atgtttactt aggtaaaggg gcataggttt tgtagttaag atgaccagac agctaaaagc tgtgatggga agtatggact gctcctattt atagtctcag aaaatggacc tttaggtctc tatccgtatt ggcaattatt agaagaaagt tacacccttt tgaaactaca aaagctgtct tggaatttcc ccctcttctc cctatttatg tccccttaga atattttagg gagcctataa ttattttcta accaaggaaa aacttaagtc tctttaagaa gcaattactt ttcataacat cagattgaat aacccacctt gctgttcagc ccacatccta ctggaaacaa aaggtaagaa acccattttc tggttcttga ttgtttgggt ctgaattttg tttttaaaac taagctaagt ttaatgtttt ttaaaatgct gtttggaata tgaatagatt ccccgtaaaa tgatttttcc taagttttat gctttagtaa atattcagtg ctcacgtctg tgcatcatag tgcttgcgtt taatatgatt tattgtagaa tctcaacttt tcttggtgtt tgttgtcttt gaaacattgt cttggtcatt agggctggtg ttttcacatt tctgtggtca aggtggattt cttatgtgtg cctttttgct tactttgtat atgaattttg taatttaaat tgcaagtaag ttatatatat gtatttacca taaatagtat taaaagatga gaaactgtta gactgaagtt ctgttgtaac ataaccatta tttccatcac agtatgaaga ctgcaaacgc agaaaacaga ttacagtctc ttatccattt tttgaaatcc aaaaactacg aaaacaaaag attttctgtt gttgagctaa ttaaatgtga accctgacca gaaaaaaaaa aaaaaaaaaa aaaaaaaa

[0061] The following nucleotide sequence comprises the mRNA transcript encoding Homo sapiens EPS8L1 (isoform 1) (SEQ ID NO: 13) having GenBank Accession No.: NM 017729:

agagcaagga agggcagggg acctgggaag gaagttctgg aaggcagtgg ggtttgagat tggacccagg gtcaagatag aacatgaagg tgggatgagg acatgaacag aacatggcca agaaggatct gggggagcag ccaggacgag gcggagctga tccgagagga catccagggg gctctgcaca attaccgctc gggccgcggg gagcgcaggg cggcggcgct cagggccacg caggaggagt tgcagcgcga ccgctcgccc gccgctgaga ccccgcccct gcagcgccgc ccgtcagtcc gcgcagtgat cagcaccgta gagcggggcg cgggccgcgg acgaccccag gcgaagccca ttcccgaggc agaggaggcg cagaggcctg agccggtggg gacctcgagc aacgctgact cggcctcccc ggacctgggt ccccggggtc ctgacctggc ggttctgcag gcggagcggg aagtggacat cctgaaccac gtgttcgacg acgtagagag ctttgtatcg aggctgcaga agtcggcgga ggcggccagg gtgctggagc accgggaacg cggccgcagg agccggcgcc gggcggctgg ggagggcttg ctgacgctgc gggccaagcc gccctcggag gccgagtaca ccgacgtgct gcagaagatc aagtacgcct tcagcctgct ggcccggctg cgcggcaaca tcgccgaccc ctcctctccg gagctgttgc acttcctttt cgggcctctg cagatgattg tgaacacgtc gggggggccg gagttcgcga gcagtgtgcg gcggccgcat ctgacatcgg atgccgtggc gctgctgcgg gacaacgtca ctccacgtga aaacgagctc tggacctcgc tgggggactc gtggacccgc cccgggctgg agctgtcccc ggaggaggga cccccataca gacccgagtt cttcagcggc tgggagccgc cggtcactga cccgcagagc cgcgcctggg aggacccagt tgagaaacag ctacagcacg agcggaggcg ccggcagcaa agcgcccccc aggtcgctgt caatggtcac cgagacttgg agccagaatc tgagcctcag ctggagtcag agacagcagg aaaatgggtc ctgtgtaatt atgacttcca ggcccgcaac agcagtgagc tgtcggtcaa gcagcgggac gtactggagg tcctggatga cagtcgtaag tggtggaagg ttcgggaccc agcggggcag gagggatatg tgccctacaa catcctgaca ccctaccccg gaccccggct gcaccacagc caaagccctg cccgcagcct gaacagcact cctcctccac caccagcccc agccccggcc ccacctccag ctctggctcg gccccgctgg gacaggcccc gctgggacag ctgcgatagc ctcaacggct tggaccccag cgagaaggag aaattctccc agatgctcat cgtcaacgag gaactgcagg cgcgcctggc ccagggccgc tcgggaccga gccgcgcagt cccagggccc cgcgccccgg aaccgcagct cagcccgggc tcggacgcct ccgaggtccg cgcctggctg caggccaagg gctttagctc cgggaccgtg gacgcgctgg gtgtgctgac cggggcgcag cttttctcgc tgcagaagga ggagctgcgg gcggtgagcc ccgaggaggg ggcacgtgtg tacagccagg tcaccgtgca gcgctcgctg ctggaggaca aagagaaagt gtcagagctg gaggcagtga tggagaagca aaagaagaag gtggaaggcg aggtggaaat ggaggtcatt tgacctgcca ggcgcccttc gcaaagagtg acgaggcccc gtgggagaac ggactcctca gactctcccc aatagcggaa gtcgatcttc tgaaggatgg ccaatctgct ccggccctgg gatccttgct gcagtccctc cggagaggat ctggactggc tgggagtggg gagggcgtgg agacagtcta cggaaagcgc tagcagaccc ccgagagggt gcagtggagc cctgagcatt gtaatatgcg gcccagccta taaacagcct ccgtgcttag caaaaaaaaa aaaaaaaaaa aaaa

[0062] The following nucleotide sequence comprises the mRNA transcript encoding Homo sapiens EPS8L1 (isoform 2) (SEQ ID NO: 15) having GenBank Accession No.: NM 133180:

aggaggaggg gccggcagcc tggaagggaa aggacagcgg agagcagggc agagcctgag caggcagggc acctccaggt gggcaggagc taccactcag caccatgagc accgccacag gcccagaagc tgccccaaag ccaagcgcca agtctatcta tgagcagagg aagcgttact ccacagttgt tatggctgat gtatcccagt acccagtcaa tcacctggtg acgttctgcc tgggtgagga cgatggcgtg cataccgtgg aggatgcctc caggaagttg gccgtcatgg atagccaggg ccgagtctgg gcacaggaga tgctgctgcg agtgtctccc gaccatgtca cgctgctcga cccggcctcc aaggaggagc tggagtcgta cccactgggc gccatcgtgc gctgtgacgc ggtgatgcca cccggcagga gccgctcgtt gctgctgctc gtgtgccagg aacccgagcg cgcgcagccc gacgtgcact tcttccaggg cctgcgcctc ggggcggagc tgatccgaga ggacatccag ggggctctgc acaattaccg ctcgggccgc ggggagcgca gggcggcggc gctcagggcc acgcaggagg agttgcagcg cgaccgctcg cccgccgctg agaccccgcc cctgcagcgc cgcccgtcag tccgcgcagt gatcagcacc gtagagcggg gcgcgggccg cggacgaccc caggcgaagc ccattcccga ggcagaggag gcgcagaggc ctgagccggt ggggacctcg agcaacgctg actcggcctc cccggacctg ggtccccggg gtcctgacct ggcggttctg caggcggagc gggaagtgga catcctgaac cacgtgttcg acgacgtaga gagctttgta tcgaggctgc agaagtcggc ggaggcggcc agggtgctgg agcaccggga acgcggccgc aggagccggc gccgggcggc tggggagggc ttgctgacgc tgcgggccaa gccgccctcg gaggccgagt acaccgacgt gctgcagaag atcaagtacg ccttcagcct gctggcccgg ctgcgcggca acatcgccga cccctcctct ccggagctgt tgcacttcct tttcgggcct ctgcagatga ttgtgaacac gtcggggggg ccggagttcg cgagcagtgt gcggcggccg catctgacat cggatgccgt ggcgctgctg cgggacaacg tcactccacg tgaaaacgag ctctggacct cgctggggga ctcgtggacc cgccccgggc tggagctgtc cccggaggag ggacccccat acagacccga gttcttcagc ggctgggagc cgccggtcac tgacccgcag agccgcgcct gggaggaccc agttgagaaa cagctacagc acgagcggag gcgccggcag caaagcgccc cccaggtcgc tgtcaatggt caccgagact tggagccaga atctgagcct cagctggagt cagagacagc aggaaaatgg gtcctgtgta attatgactt ccaggcccgc aacagcagtg agctgtcggt caagcagcgg gacgtactgg aggtcctgga tgacagtcgt aagtggtgga aggttcggga cccagcgggg caggagggat atgtgcccta caacatcctg acaccctacc ccggaccccg gctgcaccac agccaaagcc ctgcccgcag cctgaacagc actcctcctc caccaccagc cccagccccg gccccacctc cagctctggc tcggccccgc tgggacaggc cccgctggga cagctgcgat agcctcaacg gcttggaccc cagcgagaag gagaaattct cccagatgct catcgtcaac gaggaactgc aggcgcgcct ggcccagggc cgctcgggac cgagccgcgc agtcccaggg ccccgcgccc cggaaccgca gctcagcccg ggctcggacg cctccgaggt ccgcgcctgg ctgcaggcca agggctttag ctccgggacc gtggacgcgc tgggtgtgct gaccggggcg cagcttttct cgctgcagaa ggaggagctg cgggcggtga gccccgagga gggggcacgt gtgtacagcc aggtcaccgt gcagcgctcg ctgctggagg acaaagagaa agtgtcagag ctggaggcag tgatggagaa gcaaaagaag aaggtggaag gcgaggtgga aatggaggtc atttgacctg ccaggcgccc ttcgcaaaga gtgacgaggc cccgtgggag aacggactcc tcagactctc cccaatagcg gaagtcgatc ttctgaagga tggccaatct gctccggccc tggtcttccc ccatcccggt ggacagactt aacgatcctt gctgcagtcc ctccggagag gatctggact ggctgggagt ggggagggcg tggagacagt ctacggaaag cgctagcaga cccccgagag ggtgcagtgg agccctgagc attgtaatat gcggcccagc ctataaacag cctccgtgct tagcaaaaaa aaaaaaaaaa aaaaaaa

[0063] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens RPL23 (SEQ ID NO: 17) having GenBank Accession No: NM 000978:

ggccacgtga ggagggtggg cggggcgtta aagttcatat cccagtgtcc tttgaatcga cttccttttt tcttttttcc ggcgttcaag atgtcgaagc gaggacgtgg tgggtcctct ggtgcgaaat tccggatttc cttgggtctt ccggtaggag ctgtaatcaa ttgtgctgac aacacaggag ccaaaaacct gtatatcatc tccgtgaagg ggatcaaggg acggctgaac agacttcccg ctgctggtgt gggtgacatg gtgatggcca cagtcaagaa aggcaaacca gagctcagaa aaaaggtaca tccagcagtg gtcattcgac aacgaaagtc ataccgtaga aaagatggcg tgtttcttta ttttgaagat aatgcaggag tcatagtgaa caataaaggc gagatgaaag gttctgccat tacaggacca gtagcaaagg agtgtgcaga cttgtggccc cggattgcat ccaatgctgg cagcattgca tgattctcca gtatatttgt aaaaaataaa aaaaaaaact aaacccatta aaaagtattt gtttgcaaaa aaaaaaaaaa aaaa

[0064] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens SYBLl (SEQ ID NO: 19) having GenBank Accession No: NM 005638:

gaattcgccg gtccagcctc ctctgggagc gggcagttgg cgaccctgca ctgacccgcg tccctccgtc ccgagcccgc gcgccctcag agggtgcccg gacagactga agccatggcg attctttttg ctgttgttgc cagggggacc actatccttg ccaaacatgc ttggtgtgga ggaaacttcc tggaggtgac agagcagatt ctggctaaga taccttctga aaataacaaa ctaacgtact cacatggcaa ttatttgttt cattacatct gccaagacag gattgtatat ctttgtatca ctgatgatga ttttgaacgt tcccgagcct ttaattttct gaatgagata aagaagaggt tccagactac ttacggttca agagcacaga cagcacttcc atatgccatg aatagcgagt tctcaagtgt cttagctgca cagctgaagc atcactctga gaataagggc ctagacaaag tgatggagac tcaagcccaa gtggatgaac tgaaaggaat catggtcaga aacatagatc tggtagctca gcgaggagaa agattggaat tattgattga caaaacagaa aatcttgtgg attcttctgt caccttcaaa actaccagca gaaatcttgc tcgagccatg tgtatgaaga acctcaagct cactattatc atcatcatcg tatcaattgt gttcatctat atcattgttt cacctctctg tggtggattt acatggccaa gctgtgtgaa gaaataggaa agaagaagtt accattaacc aaggatatga gagaacaagg agttaaaagc aatccatgtg actcaagcct ttcacatact gacagatggt atctgccagt ctcttcaacc ctcttctcac tttttaaaat cttgttccat gcctccaggt ttatctttgt cttatctacc agtttattcc tgtgaacttc agattgaacc attcattgca gcagtagcct taaaaaggct tttgtttatt tctttggttt gttaactagt gtcatctatt tagagaaaca tttttgtttt taattgctca aagctgtcgc cgctagtctt atgagctatc tactaaaact atggagaaac tttgtatgtg cacacaaaag tattcaagag acagtattgc taacatctca tcttaatgtc ttttgttatt gagaagtttt aggtgcttca aaacaatata aatggataat agttgttatt tggggaattg taatgatgtt ggtgctgctt ccttctaaga gctcagacaa gtaaagtatg aaacattctt atttcagtta gatggggaac attttgctag cccattagaa gcacacagaa ttatccttgt cctcctaata ttgactttca ggaataaagt tcagtgtgct gatcattcac aatacagtgg atagcttgat atcttctgtt ttcccattgc agttgatttg agaagatgaa ggtttaaata ttgttgaaag ttgcagtttt ttaaatgtgt tcctttttct tctgtgaata tttagggcaa tcgtgtcgct aatagaatat gtagtagagg gggtggggag gtaaattcct ctgacttgcc aaagaaaaag aagggaacca cagtggatat gctagcattt tagctgtgca aagggaggta gtgtgggaaa agtgtttcca ttctgggaaa agcccaaacc gaatacggtc agcagtcaac tccagggttt gggcttgatt cctgttgaat aatagttttg agcattcttt gtggttaaat aaattcttaa atctgcctag ttttgatgaa ttcttttgtg aaacttgaaa gagaatagac agtatgacat atagaattaa tacaaaacag tttaacaacc atttaactgc agtgtaagaa aattggactg taatcatatc gctactggca tctgttatct agtatgcatt tctggtgtgt atctgaaagg aagacatttt ctaccctaga tccaattgca tttatttatc aataagtgcc attaaattga aattatatta cattttacac tttctcaatg aatgaacaaa ttagtctgta gaatctagcc acctgtttag cctagtcatg tgccttgaac atatatgtgt cccataatct ggctcatggt acctgttctt ctatccaaac ctttcaattc atgctacctg attcatttat ttgacataga tcttaggccc acttgaactc ttttcttgtt tatctagcat agcacaaacg tttttccagt cttctttatc aacactaatg cctcttaatt gcatcagtat ttcctattgg aaaatacatc tgttccagaa aaacatttgg cattcctgaa taatttccaa atgtttttaa tccaaagaaa aaggtttaaa gcttatttcc ctttcttata cacacctgaa taaaattgat gtgcatgttt tagggatcaa ttacctaact gttccttggt ctatttatgt ataagaatgc tttttaaagc acatgtctca ttttaaatga cgcacaaact gaagatgtta ataaaattta aggaattc

[0065] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens DDOST (SEQ ID NO:21) having GenBank Accession No: NM 005216:

aatccacctc ccaccagggc acttccggcg gcgctctccg cgccttatcg ccaaagctgc ggctctggac gcccagccgc ggcgtatccc gatcacttcc gggtagtgct ccacgggcac gagccgcgat tgggctaccg tagatggggt acttccggtg tgcaggtgct gggtccttcg gcaggaggag gaagatggag cccagcaccg cggcccgggc ttgggccctc ttttggttgc tgctgccctt gcttggcgcg gtttgcgcca gcggaccccg caccttagtg ctgctggaca acctcaacgt gcgggagact cattcgcttt tcttccggag cctgaaggac cggggctttg agctcacatt caagaccgct gatgacccca gcctgtctct cataaagtat ggggaattcc tctatgacaa tctcatcatt ttctcccctt cggtagaaga ttttggaggc aacatcaacg tggagaccat cagtgccttt attgacggcg gaggcagtgt gctggtagct gccagctccg acattggtga ccctcttcga gagctgggca gtgagtgcgg gattgagttt gacgaggaga aaacggctgt cattgaccat cacaactatg acatctcaga ccttggccag catacgctca tcgtggctga cactgagaac ctgctgaagg ccccaaccat cgttgggaaa tcatctctaa atcccatcct ctttcgaggt gttgggatgg tggccgatcc tgataaccct ttggtgctgg acatcctgac gggctcttcc acctcttact ccttcttccc ggacaagcct atcacccagt atccacatgc ggtggggaag aacaccctcc tcattgctgg gctccaggcc aggaacaatg cccgcgtcat cttcagcggc tccctcgact tcttcagcga ctccttcttc aactcagcag tgcagaaggc ggcgcccggc tcccagaggt attcccagac aggcaactat gaactagctg tggccctctc ccgctgggtg ttcaaggagg agggtgtcct ccgtgtgggg cctgtgtccc atcatcgggt gggcgagaca gccccaccca atgcctacac tgtcactgac ctagtggagt atagcatcgt gatccagcag ctctcaaatg gcaaatgggt cccctttgat ggcgatgaca ttcagctgga gtttgtccgc attgatcctt ttgtgaggac cttcctgaag aagaaaggtg gcaaatacag tgttcagttc aagttgcccg acgtgtatgg tgtattccag tttaaagtgg attacaaccg gctaggctac acacacctgt actcttccac tcaggtatcc gtgcggccac tccagcacac gcagtatgag cgcttcatcc cctcggccta cccctactac gccagcgcct tctccatgat gctggggctc ttcatcttca gcatcgtctt cttgcacatg aaggagaagg agaagtccga ctgaggggct agagccctct ccgcacagcg tggagacggg gcaaggaggg gggttattag gattggtggt tttgttttgc tttgtttaaa gccgtgggaa aatggcacaa ctttacctct gtgggagatg caacactgag agccaagggg tgggagttgg gataattttt atataaaaga agtttttcca ctttgaattg ctaaaagtgg catttttcct atgtgcagtc actcctctca tttctaaaat agggacgtgg ccaggcacgg tggctcatgc ctgtaatccc agcactttgg gaggccgagg caggcggctc acgaggtcag gagatcgaga ctatcctggc taacacggta aaaccctgtc tctactaaaa gtacaaaaaa ttagctgggc gtggtggtgg gcacctgtag tcccagctac tcgggaggct gaggcaggag aaaggcatga atccaagagg cagagcttgc agtgagctga gatcacgcca ttgcactcca gcctgggcaa cagtgttaag actctgtctc aaatataaat aaataaataa ataaataaat aaataaataa aaataaagcg agatgttgcc ctcaaacttc acctggaaaa aaaaaaaaaa aaaa

[0066] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens SATBl protein (SEQ ID NO:23) having GenBank Accession No: NM 002971 :

ttctgccctt cccccgctta ggggggcggg ggtaggggaa aggaaaataa tacaatttca ggggaagtcg ccttcaggtc tgctgctttt ttattttttt tttttaatta aaaaaaaaaa ggacatagaa aacatcagtc ttgaacttct cttcaagaac ccgggctgca aaggaaatct cctttgtttt tgttatttat gtgctgtcaa gttttgaagt ggtgatcttt agacagtgac tgagtatgga tcatttgaac gaggcaactc aggggaaaga acattcagaa atgtctaaca atgtgagtga tccgaagggt ccaccagcca agattgcccg cctggagcag aacgggagcc cgctaggaag aggaaggctt gggagtacag gtgcaaaaat gcagggagtg cctttaaaac actcgggcca tctgatgaaa accaacctta ggaaaggaac catgctgcca gttttctgtg tggtggaaca ttatgaaaac gccattgaat atgattgcaa ggaggagcat gcagaatttg tgctggtgag aaaggatatg cttttcaacc agctgatcga aatggcattg ctgtctctag gttattcaca tagctctgct gcccaggcca aagggctaat ccaggttgga aagtggaatc cagttccact gtcttacgtg acagatgccc ctgatgctac agtagcagat atgcttcaag atgtgtatca tgtggtcaca ttgaaaattc agttacacag ttgccccaaa ctagaagact tgcctcccga acaatggtcg cacaccacag tgaggaatgc tctgaaggac ttactgaaag atatgaatca gagttcattg gccaaggagt gccccctttc acagagtatg atttcttcca ttgtgaacag tacttactat gcaaatgtct cagcagcaaa atgtcaagaa tttggaaggt ggtacaaaca tttcaagaag acaaaagata tgatggttga aatggatagt ctttctgagc tatcccagca aggcgccaat catgtcaatt ttggccagca accagttcca gggaacacag ccgagcagcc tccatcccct gcgcagctct cccatggcag ccagccctct gtccggacac ctcttccaaa cctgcaccct gggctcgtat caacacctat cagtcctcaa ttggtcaacc agcagctggt gatggctcag ctgctgaacc agcagtatgc agtgaataga cttttagccc agcagtcctt aaaccaacaa tacttgaacc accctccccc tgtcagtaga tctatgaata agcctttgga gcaacaggtt tcgaccaaca cagaggtgtc ttccgaaatc taccagtggg tacgcgatga actgaaacga gcaggaatct cccaggcggt atttgcacgt gtggctttta acagaactca gggcttgctt tcagaaatcc tccgaaagga agaggacccc aagactgcat cccagtcttt gctggtaaac cttcgggcta tgcagaattt cttgcagtta ccggaagctg aaagagaccg aatataccag gacgaaaggg aaaggagctt gaatgctgcc tcggccatgg gtcctgcccc cctcatcagc acaccaccca gccgtcctcc ccaggtgaaa acagctacta ttgccactga aaggaatggg aaaccagaga acaataccat gaacattaat gcttccattt atgatgagat tcagcaggaa atgaagcgtg ctaaagtgtc tcaagcactg tttgcaaagg ttgcagcaac caaaagccag ggatggttgt gcgagctgtt acgctggaaa gaagatcctt ctccagaaaa cagaaccctg tgggagaacc tctccatgat ccgaaggttc ctcagtcttc ctcagccaga acgtgatgcc atttatgaac aggagagcaa cgcggtgcat caccatggcg acaggccgcc ccacattatc catgttccag cagagcagat tcagcaacag cagcagcaac agcaacagca gcagcagcag cagcaggcac cgccgcctcc acagccacag cagcagccac agacaggccc tcggctcccc ccacggcaac ccacggtggc ctctccagca gagtcagatg aggaaaaccg acagaagacc cggccacgaa caaaaatttc agtggaagcc ttgggaatcc tccagagttt catacaagac gtgggcctgt accctgacga agaggccatc cagactctgt ctgcccagct cgaccttccc aagtacacca tcatcaagtt ctttcagaac cagcggtact atctcaagca ccacggcaaa ctgaaggaca attccggttt agaggtcgat gtggcagaat ataaagaaga ggagctgctg aaggatttgg aagagagtgt ccaagataaa aatactaaca cccttttttc agtgaaacta gaagaagagc tgtcagtgga aggaaacaca gacattaata ctgatttgaa agactgagat aaaagtattt gtttcgttca acagtgccac tggtatttac taacaaaatg aaaagtccac cttgtcttct ctcagaaaac ctttgttgtt cattgtttgg ccaatgaatc ttcaaaaact tgcacaaaca gaaaagttgg aaaaggataa tacagactgc actaaatgtt ttcctctgtt ttacaaactg cttggcagcc ccaggtgaag catcaaggat tgtttggtat taaaatttgt gttcacggga tgcaccaaag tgtgtacccc gtaagcatga aaccagtgtt ttttgttttt tttttagttc ttattccgga gcctcaaaca agcattatac cttctgtgat tatgatttcc tctcctataa ttatttctgt agcactccac actgatcttt ggaaacttgc cccttattta aaaaaaaaaa agaaaaaaaa gagtttgtta ctctattgta tgttacaaaa gaactataga ctgtggaatg cagtttaaag atgacatatg ccaacaaatg ccttgtatta tatggcactg ccgtaattca aatttgtttt tattttggaa ataaaagttc actgtacttt tttttcattc tcattgttac atgatttttt aaaaaaagga aaagaaaatg tgaaacacaa tttagtcctc attatttatt tgtagatcct gcagcatcat gttgtaatta attttttgga agtttccgtt aaatgtaata ttgcttctct tgttaccata ctgattcttt tctatttata aatgtatttt gatgggcagt aaaacaaagt gtcttaaaag ttttaaatag agaaaatgtg ctttacacag ttgcctataa aaagtgctct atgttatcca agcaattcat actataagct tcactcttat tgttgtatgc aatttttact atcatgcaaa taagcttagg taaataaaac taatagatca ccttagaaaa ttatgcaatt aatgtgaaaa taattgatgt ttgcaatgtg tcttcctttg gtttacaatc aattttaaag ctacatctgt ataaaatttc tgtataaagg tgtatttctt ttttatgagt ttatggctat gaaaacagct attttgttac agctggctgt ttttataagt gtatcacaat tttctttatg cagaaatgtt ctgactagga gtggttattg actgtaacta cacaattaaa attgtttgta tcgtaaaaaa aaaaaaaaaa aa [0067] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens INPP4B variant 1 (SEQ ID NO:25) having GenBank Accession No: NM 003866:

gaagccagag gctgggggag ctgctggagc ctcgcgaagc cgcggccggc gccctgcgcc gtcgccgccg cctgctagtt tcctccgggt tctcagcccc gggtactgag gcttcggtct ataaatagca ggttacagct cctcctgggc gcgcacacgc tcacacgctc gcaagcgaac gcaggaaagt caggctaaaa gtgtctgctg ctgctgccgc cccccactcc gcctccggga gagaatacaa agaaatggtg ttacctggca agaggtcttc tgtcttttat gaaaaattag acaaaggctt tacaggaggc atagtactgg aaatctgctc ctgatgaggt ctcagaaagc ttccactcgt ggtggaaggc aaaggaggag caggcacatc acatgagcct tgaaaccagc gaaacaataa tcaaagagca gttctgtcaa agaaaacaac ataaatcagg tacagaattt cagagtggga tatcagatct ttagtgtgaa gatacatcta cattaaacca ggaatcacta gaactgacat ttggacaaga aaatttggaa aattttaaaa ctgtgaaggt tgatcatgga aattaaagag gaaggggcat cagaagaagg gcagcacttt cttcctacag cccaggccaa tgatcccggg gactgtcagt tcacaagtat ccagaagact ccaaatgaac cgcagttgga attcatcctt gcatgcaagg atctcgtggc tcctgtccgt gatcgtaaac tgaatacact ggtgcagatc tccgtaatcc accccgtgga gcagagtctg acaagatact ccagcaccga aattgtggag ggaacaaggg acccactgtt tttgactggt gtcacattcc catctgagta tcccatctat gaggagacca aaataaaact aacagtctat gatgtcaagg ataagtctca tgacaccgtt cgaaccagtg tcctaccaga acataaggat cccccgccag aagttgggcg aagtttcttg ggctatgcca gttttaaagt gggagagctg ctgaagtcaa aggagcaatt gctggtcctg agcctgagaa cttcagatgg tggcaaagtg gttggcacca tagaagtcag tgtcgtgaag atgggggaga ttgaggatgg ggaagccgac cacatcacca cagatgtaca gggacaaaag tgtgccctgg tatgtgaatg tacagccccg gaaagtgtga gcggaaaaga taacttacct tttttgaatt cagtgttaaa gaacccagta tgtaaattat atagatttcc cacatctgac aataagtgga tgcgaattcg agagcagatg tcagagagca ttctttcctt tcatattcct aaggaattga tttcccttca cattaaagaa gatttgtgca gaaaccagga gataaaagaa cttggtgagc tttctccaca ttgggacaat ctgcgaaaaa atgtccttac tcactgtgat caaatggtga atatgtacca agacattctg acagaactta gcaaggaaac agggtcctct ttcaaatcaa gcagcagcaa aggagagaaa acattagaat ttgttccaat aaatctacat ctgcaaagaa tgcaggtaca cagccctcac ttgaaagatg ctctctacga tgtcatcact gtgggagccc cagctgccca ttttcaggga tttaagaatg gtggtcttcg gaagctactc catagatttg aaacagaaag aagaaatacc ggataccagt ttatttacta ttcacctgaa aacacagcca aagcaaagga agttctcagc aacatcaatc aactacaacc tcttatagca acccatgcag acctactgct taattctgca agccagcatt ctccagacag cttgaagaat tctttaaaga tgctttcaga aaaaacagag ctttttgtac atgccttcaa ggatcaactt gtcaggagtg ctcttttagc actctacact gcaaggccag gaggcattct taagaagcca ccctctccta agagcagcac agaggagagc agtccccaag accaaccccc agtgatgaga gggcaggact ccataccaca tcattcagac tatgatgagg aagagtggga cagggtgtgg gccaatgtgg ggaagagcct gaactgcatt attgctatgg tggacaaact gattgaaaga gatggtggca gtgaaggcag tggcggcaac aatgatggag aaaaggaacc ttcattaaca gatgccattc cctctcaccc aagagaggac tggtatgaac agttgtatcc cctcatcctt accctgaagg actgcatggg agaagtggtg aaccgagcca agcagtccct gacatttgtg ctccttcagg aacttgcgta cagcttgccc cagtgtctga tgctgacgct aagaagagac atcgtcttca gccaagcact tgctggattg gtttgtggtt ttatcatcaa attacagaca agtctgtatg acccaggctt cctacagcag cttcacacag tggggttgat agtacaatat gaaggactgc taagtacata cagcgatgaa attggaatgc tagaggacat ggccgttggc atttccgatt taaagaaagt tgcatttaaa ataattgaag ccaaatccaa tgatgtgttg ccagttataa caggaagacg agaacattac gtggtagagg tcaagcttcc agccagaatg tttgagtcac tacctctaca gattaaagaa ggacagttgc ttcatgtgta tccagtactt tttaatgttg gaatcaatga acagcaaact ctggctgaaa ggtttggaga tgtctctttg caagaaagta ttaatcagga aaacttcgaa cttctacaag aatattacaa gatatttatg gaaaagatgc ctcctgatta tatttcacat tttcaggaac aaaatgattt aaaagcattg ctagaaaatc tccttcaaaa tatccaatcc aaaaaaagaa agaatgtaga aattatgtgg ctggctgcaa cgatttgccg caaactgaat ggtattcgtt tcacctgttg taaaagtgcc aaagacagga catcgatgtc agtgacactt gaacaatgct caatcttgag agatgagcac cagttacaca aggacttctt tatccgagcg ctggattgca tgagaagaga aggatgccgc atagagaatg tactgaagaa tatcaaatgc agaaagtatg ctttcaacat gctacagctg atggctttcc ccaagtacta cagacctcca gaggggactt atggaaaagc tgacacctaa gtttaccaac atgttaataa acaggaacac aaatacattt cagttggata atcttcacct tggtcttttt tgtttgtttt tattgtcatg aatttgtggt gggggagatg atcacagatg tttcccaaaa tctaggaact acttcaattc atcatcagca tattgctctg aaagaaatcc attttaaaaa atcttacatg attcagtact gtcatttcta gttctaagct tctatgtgtt gagcctagct gattgagatt ggttcacaaa gtgtaaattt cattcatgag tatttaaatg tttctgagga aacatggatc atttcaatag gactaggggt gattcacaga gcaccactct ccaaccaaat ggaagagagg agagggggaa aaggaacata ttttttttgt gatacaactt aatagcctat gagaacacag tcaacctgag aatcaatgta agggatttaa aaaaaatgtg tagccactca attaggtaga gttaactcat gatctggaat actgaggcag tttgcaggta tgttccacaa tgatctctat catccagtca aggtgtgact cctcccttgc aacaggcata tgcatggagt gagtaaagtg gtcaacagac ctttcaaaac catggcatct tttcagaact ctgacttggg ttgtgtgatc tagctgtgaa tgtagcaata tagaacgttt aatagaatga taagcaaaac actgcaatga tctaaaatta caaaaaaaaa aaaaaaaaaa

[0068] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens INPP4B variant 2 (SEQ ID NO:27) having GenBank Accession No: NM 001101669:

gaagccagag gctgggggag ctgctggagc ctcgcgaagc cgcggccggc gccctgcgcc gtcgccgccg cctgctagtt tcctccgggt tctcagcccc gggtactgag gcttcggtct ataaatagca ggttacagct cctcctgggc gcgcacacgc tcacacgctc gcaagcgaac gcaggaaagt caggctaaaa gtgtctgctg ctgctgccgc cccccactcc gcctccggga gagaatacaa agaaatggtg ttacctggca agaggtcttc tgtcttttat gaaaaattag acaaagagcc ttgaaaccag cgaaacaata atcaaagagc agttctgtca aagaaaacaa cataaatcag gtacagaatt tcagagtggg atatcagatc tttagtgtga agatacatct acattaaacc aggaatcact agaactgaca tttggacaag aaaatttgga aaattttaaa actgtgaagg ttgatcatgg aaattaaaga ggaaggggca tcagaagaag ggcagcactt tcttcctaca gcccaggcca atgatcccgg ggactgtcag ttcacaagta tccagaagac tccaaatgaa ccgcagttgg aattcatcct tgcatgcaag gatctcgtgg ctcctgtccg tgatcgtaaa ctgaatacac tggtgcagat ctccgtaatc caccccgtgg agcagagtct gacaagatac tccagcaccg aaattgtgga gggaacaagg gacccactgt ttttgactgg tgtcacattc ccatctgagt atcccatcta tgaggagacc aaaataaaac taacagtcta tgatgtcaag gataagtctc atgacaccgt tcgaaccagt gtcctaccag aacataagga tcccccgcca gaagttgggc gaagtttctt gggctatgcc agttttaaag tgggagagct gctgaagtca aaggagcaat tgctggtcct gagcctgaga acttcagatg gtggcaaagt ggttggcacc atagaagtca gtgtcgtgaa gatgggggag attgaggatg gggaagccga ccacatcacc acagatgtac agggacaaaa gtgtgccctg gtatgtgaat gtacagcccc ggaaagtgtg agcggaaaag ataacttacc ttttttgaat tcagtgttaa agaacccagt atgtaaatta tatagatttc ccacatctga caataagtgg atgcgaattc gagagcagat gtcagagagc attctttcct ttcatattcc taaggaattg atttcccttc acattaaaga agatttgtgc agaaaccagg agataaaaga acttggtgag ctttctccac attgggacaa tctgcgaaaa aatgtcctta ctcactgtga tcaaatggtg aatatgtacc aagacattct gacagaactt agcaaggaaa cagggtcctc tttcaaatca agcagcagca aaggagagaa aacattagaa tttgttccaa taaatctaca tctgcaaaga atgcaggtac acagccctca cttgaaagat gctctctacg atgtcatcac tgtgggagcc ccagctgccc attttcaggg atttaagaat ggtggtcttc ggaagctact ccatagattt gaaacagaaa gaagaaatac cggataccag tttatttact attcacctga aaacacagcc aaagcaaagg aagttctcag caacatcaat caactacaac ctcttatagc aacccatgca gacctactgc ttaattctgc aagccagcat tctccagaca gcttgaagaa ttctttaaag atgctttcag aaaaaacaga gctttttgta catgccttca aggatcaact tgtcaggagt gctcttttag cactctacac tgcaaggcca ggaggcattc ttaagaagcc accctctcct aagagcagca cagaggagag cagtccccaa gaccaacccc cagtgatgag agggcaggac tccataccac atcattcaga ctatgatgag gaagagtggg acagggtgtg ggccaatgtg gggaagagcc tgaactgcat tattgctatg gtggacaaac tgattgaaag agatggtggc agtgaaggca gtggcggcaa caatgatgga gaaaaggaac cttcattaac agatgccatt ccctctcacc caagagagga ctggtatgaa cagttgtatc ccctcatcct taccctgaag gactgcatgg gagaagtggt gaaccgagcc aagcagtccc tgacatttgt gctccttcag gaacttgcgt acagcttgcc ccagtgtctg atgctgacgc taagaagaga catcgtcttc agccaagcac ttgctggatt ggtttgtggt tttatcatca aattacagac aagtctgtat gacccaggct tcctacagca gcttcacaca gtggggttga tagtacaata tgaaggactg ctaagtacat acagcgatga aattggaatg ctagaggaca tggccgttgg catttccgat ttaaagaaag ttgcatttaa aataattgaa gccaaatcca atgatgtgtt gccagttata acaggaagac gagaacatta cgtggtagag gtcaagcttc cagccagaat gtttgagtca ctacctctac agattaaaga aggacagttg cttcatgtgt atccagtact ttttaatgtt ggaatcaatg aacagcaaac tctggctgaa aggtttggag atgtctcttt gcaagaaagt attaatcagg aaaacttcga acttctacaa gaatattaca agatatttat ggaaaagatg cctcctgatt atatttcaca ttttcaggaa caaaatgatt taaaagcatt gctagaaaat ctccttcaaa atatccaatc caaaaaaaga aagaatgtag aaattatgtg gctggctgca acgatttgcc gcaaactgaa tggtattcgt ttcacctgtt gtaaaagtgc caaagacagg acatcgatgt cagtgacact tgaacaatgc tcaatcttga gagatgagca ccagttacac aaggacttct ttatccgagc gctggattgc atgagaagag aaggatgccg catagagaat gtactgaaga atatcaaatg cagaaagtat gctttcaaca tgctacagct gatggctttc cccaagtact acagacctcc agaggggact tatggaaaag ctgacaccta agtttaccaa catgttaata aacaggaaca caaatacatt tcagttggat aatcttcacc ttggtctttt ttgtttgttt ttattgtcat gaatttgtgg tgggggagat gatcacagat gtttcccaaa atctaggaac tacttcaatt catcatcagc atattgctct gaaagaaatc cattttaaaa aatcttacat gattcagtac tgtcatttct agttctaagc ttctatgtgt tgagcctagc tgattgagat tggttcacaa agtgtaaatt tcattcatga gtatttaaat gtttctgagg aaacatggat catttcaata ggactagggg tgattcacag agcaccactc tccaaccaaa tggaagagag gagaggggga aaaggaacat attttttttg tgatacaact taatagccta tgagaacaca gtcaacctga gaatcaatgt aagggattta aaaaaaatgt gtagccactc aattaggtag agttaactca tgatctggaa tactgaggca gtttgcaggt atgttccaca atgatctcta tcatccagtc aaggtgtgac tcctcccttg caacaggcat atgcatggag tgagtaaagt ggtcaacaga cctttcaaaa ccatggcatc ttttcagaac tctgacttgg gttgtgtgat ctagctgtga atgtagcaat atagaacgtt taatagaatg ataagcaaaa cactgcaatg atctaaaatt acaaaaaaaa aaaaaaaaaa a

[0069] The following nucleotide sequence comprises the mRNA transcript encoding the Homo sapiens PHF15 (SEQ ID NO:29) having GenBank Accession No: NM 015288:

ctctcttgct cgctcgctcc ctctctctcc tgctggctgc ctgttctagg aagccagcgc ggagaggggg gggatgcaca gcacagggga gagagattgc gcatgttggt cagtcgtgtt ttaaagagta cagtgcgggg aggctgagag gggcgcatgc aacaacaact tttggaagga tggaagagaa gaggcgaaaa tactccatca gcagtgacaa ctctgacacc actgacagtc atgcgacatc tacatccgca tcaagatgct ccaaactgcc cagcagcacc aagtcgggct ggccccgaca gaacgaaaag aagccctccg aggttttccg gacagacttg atcacagcca tgaagatccc ggactcatac cagctcagcc cggatgacta ctacatcctg gcagacccat ggcgacagga atgggagaaa ggtgtgcagg tgcctgccgg ggcagaggcc atcccagagc ccgtggtgag gatcctccca ccactggaag gcccccctgc ccaggcatcc ccgagcagca ccatgcttgg tgagggctcc cagcctgatt ggccaggggg cagccgctat gacttggacg agattgatgc ctactggctg gagctcatca actcggagct taaggagatg gagaggccgg agctggacga gctgacatta gagcgtgtgc tggaggagct ggagaccctg tgccaccaga atatggccag ggccattgag acgcaggagg ggctgggcat cgagtacgac gaggatgttg tctgcgacgt gtgtcgctct cctgagggcg aggatggcaa cgagatggtc ttctgtgaca agtgcaacgt ctgtgtgcat caggcatgct acgggatcct caaggtgccc acgggcagct ggctgtgccg gacgtgtgcc ctgggtgtcc agccaaagtg cctgctctgc cccaagcgag gaggagcctt gaagcccact agaagtggga ccaagtgggt gcatgtcagc tgtgccctat ggattcctga ggtcagcatc ggctgcccag agaagatgga gcccatcacc aagatctcgc atatcccagc cagccgctgg gctctgtcct gcagcctctg caaggaatgc acaggcacct gcatccagtg ttccatgcct tcctgcgtca cagcgttcca tgtcacatgc gcctttgacc acggcctgga aatgcggact atattagcag acaacgatga ggtcaagttc aagtcattct gccaggagca cagtgacggg ggcccacgta atgagcccac atctgagccc acggaaccca gccaggctgg cgaggacctg gaaaaggtga ccctgcgcaa gcagcggctg cagcagctag aggaggactt ctacgagctg gtggagccgg ctgaggtggc tgagcggctg gacctggctg aggcactggt cgacttcatc taccagtact ggaagctgaa gaggaaagcc aatgccaacc agccgctgct gacccccaag accgacgagg tggacaacct ggcccagcag gagcaggacg tcctctaccg ccgcctgaag ctcttcaccc atctgcggca ggacctagag agggttagaa atctgtgcta catggtgaca aggcgcgaga gaacgaaaca cgccatctgc aaactccagg agcagatatt ccacctgcag atgaaactta ttgaacagga tctgtgtcga ggcctgtcca cctcattccc catcgatggc accttcttca acagctggct ggcacagtcg gtgcagatca cagcagagaa catggccatg agcgagtggc cactgaacaa tgggcaccgc gaggaccctg ctccagggct gctgtcagag gaactgctgc aggacgagga gacactgctc agcttcatgc gggacccctc gctgcgacct ggtgaccctg ctaggaaggc ccgaggccgc acccgcctgc ctgccaagaa gaaaccacca ccaccaccac cgcaggacgg gcctggttca cggacgactc cagacaaagc ccccaagaag acctggggcc aggatgcagg cagtggcaag gggggtcaag ggccacctac caggaagcca ccacgtcgga catcttctca cttgccgtcc agccctgcag ccggggactg tcccatccta gccacccctg aaagcccccc gccactggcc cctgagaccc cggacgaggc agcctcagta gctgctgact cagatgtcca agtgcctggc cctgcagcaa gccctaagcc tttgggccgg ctccggccac cccgcgagag caaggtaacc cggagattgc cgggtgccag gcctgatgct gggatgggac caccttcagc tgtggctgag aggcccaagg tcagcctgca ttttgacact gagactgatg gctacttctc tgatggggag atgagcgact cagatgtaga ggccgaggac ggtggggtgc agcggggtcc ccgggaggca ggggcagagg aggtggtccg catgggcgta ctggcctcct aactcacccc cttccctgtc ccaggccctg ccctggtccc cccacaaggc ctcagcccag tcacaactgc catttccagt ctctgctgag tgtcccagac cctcgaggct gccactccgt cgtggtttta tttttaatat agagagagtt ttgaattcta cactgttgtc tttcctctgt gctggcctag gacattagga ttccttccac ggctccggcc gctaggaccc tgccaggtcc cgcgcaccat ccctgccctg cccacgtggt attgctgggc tcctggctag atgcaagcaa ggtggacaag agctcaggac tccagcccac tgccactggg tgacacagac tgtcgtttgg gcattatttc atggcagatg ggccagtcca gggcctaccc cgccttgccc ccagatccca ctggggtcca tttggggggt cctgctacac tccaccgatc cccaaggaag tataataaac gatacccagc cagagtctac tcactgtcac aagcacaacg agtttatatg agaaagcact gagggggtgc agagggcccg ctagttccag gggaactgaa agctgttcct gatcagcccg tatcatctga ggcctgcctg cccaccctgc caccctcccc tcccttgctg ctctgcccct gccagtgccc agcccagcgg ctctgggaag gggttcccag aatccctcct gagctgtgcc atttactcag gggactccca aacagccagc tgccagtgca ggtggagggc tgtaggggag ggccagtgcc cagacagggt catggggctc agaccagccc actgtagaga atcactctga ggctccaact tccttccttc cttcggggcc agtctcggcc gaagtctggt cacgctcaga cagagctgac cagaccagac cgtttgcctt ttcaagtttc ctagtcctgc tacaagatga gcttcttccg tggtttcctt ttggaaactc ctccttccaa caagcagtgg gatcccgggg cccagggcgg gccggtgttg gccgctgggg ctgttgtaag tcttgctgga tgttcccctg ttcctgagcc ttaacccctc gcacagccat cccccccccc gtcctgccat ccccccccgc cgtcctgcct tccccacccc acccttaggt cccaggtagt tgctctgaag agtttcagta gagtggcccc agggtgatag ctcagggaac aacaaaaaag gaattccgtg aaaacatttt tttttctttg atgaattact cctgggtcac ttccaccact ggtaaagcca gaacttctcc aaaaagaacc ttgcaaaaag tccagtgaat cagtcgaatc attctgtgga tgccaaagaa tattttgacc ataatacagc acagcctgga cctgacaact tgtcatttgg actttttttt aaatggagtt ctttagcaac aaagtataga aacatgttca ttgcacacac ccaaggagaa gagctcaagc gcttggaaga ggatgctttg ctgctgctga agtgtacctg ggtgttagat ttcagatcct gggctgagcc cactgtgagc tttcctaaac tgtgagactc acagagggga aagatactga cggtgaaacc agcatggaaa acgtctttac catgtggttc cctcctcccc aaatacataa agcaaataag caggatgggg aacagcttga ccttcatcca cccctaactc caaaactatc aaggtacgac agtggcattg tcatcgacac tcaatttcat gtgaatttta gcaaaacagg aaacaaagat aatgactcag ttcagaggat cggacaaatg tgtctagtcc gggtggactc ggagggagtg gggtgggctt caaggattct gggcgttggg atggcatgag ctaccctgta gagtttagtc tgcctgcccg ccttggtagt agtgaccagt cagtgtcagc atcagtgtcc caaccccagt ctctgtttac tgcctttgaa cagaacttct tccttcccca tgctttgggt cacctcgggc tgcaaccctg tctgtgccag attgcccggt ctgaccctgc aggaagcaaa gaggtgagct taaagaacaa ccaaactctg ccaggggtcc cagaaagccc agggtccagc agtctcagca cttggcccct tgccccttca caccatcctg gggcaggggc tgggcctccc tggtggcagg ggtgggtgga gaattaggga gagggtgcaa cgagtctggc cccttgcctc gggctggctg gtgttcttcc aagagcctct gctcacattg ttggcctctg gattctggcc cttcttcatt ggctgttgct ttggactgga ctgttgctga gcctgtgtcc tgcagaaccc agatgtctgt taggctggct ggctgctgcg aggggagggg ggtggccttt catttggggt gccctttcac tcccaggcca agccctggag caatcttctt caggcagctg tctccacctc caggatgtcc agcaggctgc aaggagaagg atgccagcca cccatcctcc cccagttccc agcctttccc ctgttggtca cagccgcttc tgtctttttc cggtctactg tccccagtgt agagggcttt gctgtccctg agactgaggc aggttccttt tccaggtcag aggtggaggt agatctttct ctcaaccaca tctgcctcca cacacagctc ctccgcaggg aaggagaagc tgctctgtaa ctcattctgg ctatcgtccc ccttctcact gacctgaccg cccaccacct ccttccccct catcacatga caaaggataa tgtgcaagaa aagtattttt atgtatcata aatgtatttt gaaacaaatg agaagaagaa aggtagaagg gtttatttta ttaaatgagc ctgacttagt gacagtgtgt gagcatttgc aatgtaaggg cctcagcttc cttggagaag ccaccccagg tttccagaca tagatgttga attgtttgtg gggggtgtgc caggccacgt ctcgtgtgtc cgtatgcagg catgcctgtg tatactgtgt atgggcacac tgggactagc tgggacaatt cctagagatt caactgccca attctaacca acattggcag cggctgaact tggcatttcc ttgctaactg ccagatgtgg ccaacctttg tccatatgca aaccactgaa aaatgatctg gatttctata gcaaggccct tggggagggc actctcccat gcccttggcc tcgctggcca cattggccaa tgagccaggg ctggagtctg agacctttgg ttgttcttta aggcacctcc tgccactttc tccctcagag gcacaaacac tttgtgttcc acgtcagttt gaggggacgg tggggggatg atatgaatgt cacaggagga gacaccttct gtctttgttt caaagaaagt gatgtgccat ttgttaatat acaagagaaa tattgaaaat atattgaaaa gagcaatttt aaattatttt tggcttatgt tgcaatattt attttcttgt attagaaaag attcctttgt agagaaaaaa tgtatttttc attaacgcaa agacctattt ctcctttttg tacattgtcc atgtgcgcaa cccttaacga gcaatagaat gtatggtcac ctgggtgtgg ccagtgcccg ctgtgccctg catgattctg tgttgccgct gctgcatagt tcccagcccc atcctgtcct gctcactcat gggggcttcc agaccccggc cccaccaggg cttgtgtcat agggagccct ttgcactcct cgtgtgttgg caaacgcagt taataaagca gtgttttctg tgc

[0070] In some embodiments of the invention, the nucleotide sequence of a suitable fragment of the gene is used, or an oligonucleotide derived thereof. The length of the oligonucleotide of any suitable length. A suitable length can be at least 10 nucleotides, 20 nucleotides, 50 nucleotides, 100 nucleotides, 200 nucleotides, or 400 nucleotides, and up to 500 nucleotides or 700 nucleotides. A suitable nucleotide is one which binds specifically to a nucleic acid encoding the target gene and not to the nucleic acid encoding another gene.

[0071] An increase in the expression level of ANXAl in the patient sample, as compared to the expression level of ANXAl in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is sensitive to treatment with a PLKl kinase inhibitor.

[0072] A decrease in the expression level of one or more of ANXAl, TRAPPC4, SYBLl, DDOST, and PHF 15 in the patient sample, as compared to the expression level of each gene in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is sensitive to treatment with the a PLKl kinase inhibitor. In some embodiments, a decrease in the expression levels of any one, two, three or four of ANXAl, TRAPPC4, SYBLl, DDOST, and PHF 15 in the patient sample, as compared to the expression level of each gene in a normal tissue sample or a reference expression level (such as the average expression level of the gene in a cell line panel or a cancer cell or tumor panel, or the like), indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is resistant to treatment with a PLKl kinase inhibitor.

[0073] An increase in the expression level of a gene in the patient sample, as compared to the expression level of a gene in a normal tissue sample, and a modulation in the expression level of one or more of SFRSl, EPS8L1, RPL23, SATBl, or INPP4B, in the patient sample, as compared to the expression level of each gene in the normal tissue sample, indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is either resistant to treatment with a PLKl kinase inhibitor. In some embodiments, decrease in the expression level of SFRSl, and a decrease in the expression levels of any one, two, three or four of EPS8L1, RPL23, SATBl, and INPP4B in the patient sample, as compared to the expression level of each gene in a normal tissue sample, indicates that the cancer cell, tissue or tumor, from which the patient sample was obtained, is sensitive to treatment with a PLKl kinase inhibitor.

[0074] When the cancer is breast cancer, the cancer cell, tissue or tumor is a breast cancer cell, tissue or tumor, respectively.

[0075] A modulation in the expression level of a gene in a patient sample selected from the genes ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein increase of expression of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SYBLl, DDOST, and PHF15, and/or a decrease in the expression of one gene selected from the group consisting of SFRSl, EPS8L1, RPL23, SATBl, and INPP4B indicates a patient that is sensitive to a PLKl kinase inhibitor. In another embodiment, a modulation in the expression level of a gene in a patient sample selected from the genes ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein decrease of expression of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SYBLl, DDOST, and PHF15, and/or an increase in the expression of one gene selected from the group consisting of SFRSl, EPS8L1, RPL23, SATBl, and INPP4B indicates a patient that is resistant to a PLKl kinase inhibitor. For example, an increase in the expression level of the SFRSl gene in a patient sample; and (b) comparing the expression level of SFRS 1 from the patient with the expression level of SFRS 1 in a normal tissue sample, wherein increase of expression of SFRS 1 indicates a patient that is resistant to a PLKl kinase inhibitor. Conversely, a decrease in the expression level of the SFRSl gene in a patient sample compared to the expression level of SFRSl from the patient with the expression level of SFRSl in a normal tissue sample, indicates a patient that is sensitive to a PLKl kinase inhibitor.

[0076] In some embodiments of the invention, the method comprises: (a) measuring the expression level of one gene selected from the group consisting of the genes encoding PLKl, ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient; and (b) determining the response of the breast cancer to thiophene amide PLKl kinase inhibitor using a computational model described in co-pending International Patent Application No. PCT/US2008/059176.

[0077] In another embodiment, for any new sample, the expression levels of the above genes are measured and serve as inputs to the computational model , which then predicts GI50. If GI50 is low, the sample is sensitive to thiophene amide PLKl kinase inhibitor, and resistant if GI ₅₀ is high. In one embodiment, the computation model is described in co-pending International Patent Application No. PCT/US2008/059176, hereby incorporated by reference.

[0078] In some embodiments of the invention, the method further comprises administering a therapeutically effective amount of the PLKl kinase inhibitor to the patient. Compounds and formulations of PLKl kinase inhibitors suitable for use in the present invention, and the dosages and methods of administration thereof, are taught in U.S. Patent Nos. 6,350,747, and International Patent Application Nos. WO 2004/014899; WO2005/037827; WO2007/030366; WO2007/030361; WO2007/030359; WO2007/143456; and WO2007/143506, the contents of all which are incorporated by reference in their entireties.

[0079] In some embodiments of the invention, the PLKl kinase inhibitor is a thiophene amide such as GSK461364. [0080] In some embodiments of the invention, the thiophene amide is a substituted benzimidazole thiophene benzyl ether compound as described in WO2007/143506, which is incorporated in its entirety by reference, and teaches one method of administration of a thiophene amide PLKl inhibitor to a patient. In one embodiment, the substituted benzimidazole thiophene benzyl ether compound is GSK462364. .

EXAMPLE 1

[0081] The dose response curves for GSK461364 in a panel of 50 breast cancer cell lines are measured using the method of Neve et al. ("A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes", Cancer Cell 10:515-527, 2006), which is incorporated in its entirety by reference. The response curves are used to estimate the GI50 value for each cell line, which are then used to perform the correlative analyses for sensitivity prediction. To identify the computational model and the predictive markers of sensitivity to GSK461364, from cell-line panel, a training set of 30 cell-lines are randomly selected, which are used for further to learn the molecular markers and the computational model for sensitivity prediction. The remaining 10 cell-lines are used to test the accuracy of the model.

[0082] Genome-wide correlation of mRNA levels with the measured GI₅₀ values are performed to identify statistically significant mRNA markers (p < 5e-03, FDR < 5%). The total number of genes in this model is 10 (see Table 1). The cell lines found sensitive to GSK461364 are found in Table 2. The average Iog2(expression) of the identified genes are listed in Table 3.

[0083] Table 1.

[0084] Thus, according to Table 1 , the following biomarkers are predictive of sensitivity to a PLKl kinase inhibitor: ANXAl, TRAPPC4, SYBLl, DDOST, and PHF15. The following biomarkers are predictive of resistance to a PLKl kinase inhibitor: SFRSl, EPS8L1, RPL23, SATBl, and INPP4B.

[0085] Table 2 GI50 of GSK461364 in cell lines.

Cell Line Subtype GI50 (nM) of GSK461364

HCC1395 N/A 0.24

HBL100 Bb 0.35

SUM52PE L 0.51

MDAMB468 Ba 0.8

MDAMB231 Bb 1

SUM185PE L 1

MDAMB361 L 1

BT483 L 1.5

AU565 L 2.4

HCC1954 Ba 2.9

SUM159PT Bb 4.3

MDAMB415 L 4.8

MDAMB157 Bb 5

HCC2185 L 5

CAMA1 L 5

HCC1 187 Ba 6.3

MCF10A Bb 8.8

LY2 L 9.4

HCC3153 Ba 10

SKBR3 L 10

Hs578T Bb 11

HCC1500 Bb 11

HCC1806 N/A 12

HCC38 Bb 12

HCC1 143 Ba 12

HCC70 Ba 15

MDAMB436 Bb 18

S1 N 20

SUM229PE N/A 20

SUM149PT Bb 22

MDAMB134VI L 24

ZR75-1 L 28

MCF12A Bb 30

MCF7 L 30

184B5 N 37

HCC1419 N/A 40

BT549 Bb 40

T4 L 44

MDAMB453 L 46

HCC1569 Ba 50

ZR75B L 50

MCF10F N/A 100 Table 3.

[0086] In Table 3, the average log₂ (expression) of the genes are determined by measuring the expression levels of the genes in 51 cell lines, including the following cell lines: MDAMB415, MDAMB468, MDAMB157, MDAMB134VI, ZR75.1, SUM44PE, HCC1428, MDAMB361, MDAMB436, SUM52PE, HCC202, BT20, BT549, HCC 1937, CAMAl, MDAMB453, MCF12A, HCC70, HBLlOO, SUM225CWN, HCC38, T47D, SUM1315MO2, HCC3153, HCC1569, HCC2157, BT483, MDAMB435, MCF7, HCC1954, HCCl 187, SUM149, HCCl 143, AU565, SKBR3, MDAMB175VII, HCC1500, ZR75B, SUM159PT, HCC1008, HCC2185, LY2, SUM190PT, 600MPE, MDAMB231, BT474, UACC812, SUM185PE, HS578T, ZR7530, and MCFlOA.

EXAMPLE 2

[0087] Cell viability/proliferation was evaluated by CellTiter-Glo^® luminescent cell viability assay (CTG, Promega), cell apoptosis was assayed using YoPro-1 and Hoechst staining and cell cycle inhibition was assessed by measuring BrdU incorporation. All cellular measurements were made in adhered cells using the Cellomics high content scanning instrument. All assays were run at 3, 4, 5 and 6 days post transfection. [0088] Cell growth analysis was carried out using the CcllTiter-GIo ' Luminescent Cell Viability Ai>,say (Promega Cat#G7571/2/3). The luminescence signal of viable cells as measured the amount of ATP detected in the plates were read using a custom plate reader and program.

[0089] BrdU Staining and Fixation for Cellomics were used to measure cell proliferation and cell cycle analysis. To incorporate BrdU and fix the cells lOuM final concentration of BrdU (Sigma #B5002) was added directly to cell media and pulsed for 30 minutes in tissue culture incubator. The media was removed and the cells washed 2X with IX PBS and then 70% EtOH added to cover cells and fix for overnight at 4⁰C. Next day the 70% EtOH was removed and cells allowed to dry. Then 2N HCl was added and cells incubated at room temperature for 5-10 minutes, then removed and IX PBS added to neutralize. Diluted anti- BrdU antibody (Mouse anti-BrdU Clone 3D4 (BD Pharmingen #555627)) 1 :100 in IX PBS/0.5% Tween-20. Anti-BrdU was added to cells (50ul - 96 well plate; 200ul - 24 well plate) and incubated for 45-60 minutes at room temperature on a rocker. Antibody was aspirated and cells washed 2X with IX PBS/0.5% Tween-20. Rabbit Anti-mouse Alexa Fluor 488 (Invitrogen #A-11059) was diluted 1 :250 in IX PBS/0.5% Tween-20. Secondary antibody was added to cells and incubated 30-60 minutes at room temperature on a rocker then washed 3X with IX PBS/0.5% Tween-20. After the last wash was removed and cells were incubated with lug/ml Hoechst 33342 (Sigma #B2261) diluted in IX PBS for 45 minutes at room temperature on a rocker. Cells were washed and covered with IX PBS. Plates were scanned or stored at 4⁰C for later scanning on Cellomics.

[0090] YoPro-1 Staining for Cellomics was used for cell apoptosis analysis. Add YoPro- 1 (Final use at 1 ug/ml) and Hoechst (Final use at 10 ug/ml) directly to cell media. Place in 37 ⁰C incubator for 30 min. Then read directly on Cellomics. Figure 2 shows breast cancer cell viability measured by CellTiter-Glo® Luminescent Cell Viability Assay of selected cell lines after exposure to GSK461364 for 24h, 48h, and 72h. The cell lines MDAMB231, SUM52PE, and HCC 1954 exhibit reduced cell viability of 40% or less at least 72 hours after exposure to PLKl inhibitor, GSK461364.

[0091] Figure 3 shows the Caspase3 activity detected by Caspase3 GIo Assay (Fig3) after exposure to PLKl inhibitor, GSK461364 for 24h, 48h, and 72h. The cell lines MDAMB231, SUM52PE, HCC 1954 and HBLlOO exhibit increased caspase3 activity of 5 fold or more after exposure to 1OnM or 5OnM PLKl inhibitor, GSK461364 for 72 hours. [0092] Figure 4 shows the apoptosis rate assessed by automatic imaging analysis system with YoPro-1 and H33342 staining after breast cancer cells treated with 1OnM, 5OnM GSK46136 for 24h, 48h and 72h. The cell lines MDAMB231, SUM52PE, and HCC 1954 exhibit increased rates of apoptosis of 20% or more at least 72 hours after exposure to 1OnM or 5OnM PLKl inhibitor, GSK461364.

[0093] Figure 5 shows GSK461364 induces cell cycle G2/M arrest in sensitive breast cancer cell lines. Cell cycle was analyzed by BrdU and H33342 staining using Cellomics scanner after cells treated with PBS, DMSO and 1OnM GSK461364 for 48h.

[0094] Network analyses of genes was performed to determine which genes are associated with resistance (Fig. 6A) and sensitivity (Fig. 6B) and act as predictive biomarkers in response to GSK461364 treatment by supervising genomic and mRNA expression signatures of cell lines with the GI₅₀ profile of GSK461364.

[0095] Figure 7 shows pathway analyses of genes associated with sensitive and resistant predictive biomarkers in response to GSK461364 treatment by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK461364.The features of genes associated with GSK461364 drug resistance were found to be genes that are related to AR (Androgen Receptor) and CCNDl(Cyclin Dl) function, involved in network functions such as cell cycle progression, and involved in enriched metabolic pathways of Ascorbate and Adarate, Tryptophan, Arginine and Proline metabolism. The features of genes associated with GSK461364 drug sensitivity were found to be genes that are related to RNA Polymerase II function, involved in network functions such as cell cycle progression and transcription, and involved in enriched metabolic pathways of Inositol, Purine, and Pyrimidine metabolism.

[0096] Based on the foregoing, it was shown that GSK461364 can inhibit cell growth, induce cell apoptosis and G2/M arrest in breast cancer cells. GSK461364 is more sensitive in cell lines representing clinically aggressive basal B breast cancers sub-type than in luminal subtype cell lines or non-transformed human mammary epithelial cultures. GSK461364 response is associated with inositol metabolism, arginine and proline metabolism, ascorbate and aldarate metabolism pathways.

EXAMPLE 3

[0097] The mRNA expression levels of these genes in Glaxo SmithKline's tumor panel is obtained, and applied to a model described to predict sensitivity status of these tumors. Furthermore, the PLKl positive tumors (PLKl expression level relative to GAPDH are stratified as sensitive if predicted less than the log(GIso); others are considered resistant. The progression free survival of these predicted responders (sensitive) are compared to the non- responders (resistant). Based on the cellular response measured in the 50 breast cell line panel in Example 1 , median survival is expected to be longer for the predicted responders who are treated with GSK461364, and shorter when treated with placebo.

[0098] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

WE CLAIM:

1. A method for identifying a PLKl -positive cancer patient suitable for treatment with a PLKl kinase inhibitor, comprising: (a) measuring the expression level of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample or a reference expression level.

2. The method of claim 1, further comprising (c) measuring the expression level of a gene in a sample from the patient, and (d) comparing the expression level of the gene in the normal tissue sample or a reference expression level, or the average expression level in a panel of normal cell lines or cancer cell lines, whereby an increase of expression of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SYBLl, DDOST, and PHF15 indicates the patient is suitable for treatment with a PLKl kinase inhibitor and an increase of expression of one gene selected from the group consisting of the genes encoding SFRSl, EPS8L1, RPL23, SATBl, INPP4B, and PHF 15 indicates the patient will be resistant to treatment with a PLKl kinase inhibitor.

3. The method of claim 1, wherein step (a) comprises measuring the expression level of two genes selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient.

4. The method of claim 3, wherein step (a) comprises measuring the expression level of three genes selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient.

5. The method of claim 4, wherein step (a) comprises measuring the expression level of four genes selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF15 in a sample from the patient.

6. The method of claim 5, wherein step (a) comprises measuring the expression levels of the genes encoding ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient.

7. The method of claim 1 , wherein the cancer is breast cancer.

8. The method of claim 1, further comprising administering a therapeutically effective amount of a PLKl kinase inhibitor to the patient.

9. .The method of claim 8, wherein the PLKl kinase inhibitor is a thiophene amide.

10. The method of claim 9, wherein the PLKl kinase inhibitor is a substituted benzimidazole thiophene benzyl ether compound.

11. The method of claim 9, wherein the PLKl kinase inhibitor is GSK461364.

12. A method for identifying a cancer patient suitable for treatment with GSK461364, comprising: (a) measuring the expression level of one gene selected from the group consisting of the genes encoding PLKl, ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient; and (b) determining the response of the cancer to GSK461364.

13. The method of claim 12, wherein the cancer is breast cancer.

14. The method of claim 12, wherein an increase of expression of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SYBLl, DDOST, and PHF 15 indicates the patient is suitable for treatment with a PLKl kinase inhibitor and an increase of expression of one gene selected from the group consisting of the genes encoding SFRSl, EPS8L1, RPL23, SATBl, INPP4B, and PHF15 indicates the patient will be resistant to treatment with a PLKl kinase inhibitor.

15. A method for identifying a cancer patient suitable for treatment with GSK461364, comprising: (a) measuring a modulation in the expression level of a gene in a patient sample selected from the genes ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein increase of expression of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SYBLl, DDOST, and PHF 15, and/or a decrease in the expression of one gene selected from the group consisting of SFRSl, EPS8L1, RPL23, SATBl, and INPP4B indicates a patient that is sensitive to a PLKl kinase inhibitor.

16. The method of claim 15, wherein a decrease in the expression level of the SFRSl gene in a patient sample compared to the expression level of SFRS 1 from the patient with the expression level of SFRS 1 in a normal tissue sample, indicates a patient that is sensitive to a PLKl kinase inhibitor.

17. A method for identifying a cancer patient suitable for treatment with GSK461364, comprising: (a) measuring modulation in the expression level of a gene in a patient sample selected from the genes ANXAl, TRAPPC4, SFRSl, EPS8L1, RPL23, SYBLl, DDOST, SATBl, INPP4B, and PHF 15 in a sample from the patient; and (b) comparing the expression level of said gene from the patient with the expression level of the gene in a normal tissue sample, wherein decrease of expression of one gene selected from the group consisting of the genes encoding ANXAl, TRAPPC4, SYBLl, DDOST, and PHF 15, and/or an increase in the expression of one gene selected from the group consisting of SFRSl, EPS8L1, RPL23, SATBl, and INPP4B indicates a patient that is resistant to a PLKl kinase inhibitor.

18. The method of claim 17, wherein an increase in the expression level of the SFRSl gene in a patient sample; and (b) comparing the expression level of SFRS 1 from the patient with the expression level of SFRSl in a normal tissue sample, wherein increase of expression of SFRSl indicates a patient that is resistant to a PLKl kinase inhibitor.