Comprehensive Functional Annotation of 77 Prostate Cancer Risk Loci

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Genome-wide association studies (GWAS) have revolutionized the field of cancer genetics, but the causal links between increased genetic risk and onset/progression of disease processes remain to be identified. Here we report the first step in such an endeavor for prostate cancer. We provide a comprehensive annotation of the 77 known risk loci, based upon highly correlated variants in biologically relevant chromatin annotations— we identified 727 such potentially functional SNPs. We also provide a detailed account of possible protein disruption, microRNA target sequence disruption and regulatory response element disruption of all correlated SNPs at . 88% of the 727 SNPs fall within putative enhancers, and many alter critical residues in the response elements of transcription factors known to be involved in prostate biology. We define as risk enhancers those regions with enhancer chromatin biofeatures in prostate-derived cell lines with prostate-cancer correlated SNPs. To aid the identification of these enhancers, we performed genomewide ChIP-seq for H3K27-acetylation, a mark of actively engaged enhancers, as well as the transcription factor TCF7L2. We analyzed in depth three variants in risk enhancers, two of which show significantly altered androgen sensitivity in LNCaP cells. This includes rs4907792, that is in linkage disequilibrium () with an eQTL for NUDT11 (on the X chromosome) in prostate tissue, and rs10486567, the index SNP in intron 3 of the JAZF1 gene on chromosome 7. Rs4907792 is within a critical residue of a strong consensus androgen response element that is interrupted in the protective allele, resulting in a 56% decrease in its androgen sensitivity, whereas rs10486567 affects both NKX3-1 and FOXA-AR motifs where the risk allele results in a 39% increase in basal activity and a 28% fold-increase in androgen stimulated enhancer activity. Identification of such enhancer variants and their potential target genes represents a preliminary step in connecting risk to disease process.

Vyšlo v časopise: Comprehensive Functional Annotation of 77 Prostate Cancer Risk Loci. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004102
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004102

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Zdroje

1. ManolioTA (2010) Genomewide association studies and assessment of the risk of disease. The New England journal of medicine 363: 166–176.

2. CoetzeeSG, RhieSK, BermanBP, CoetzeeGA, NoushmehrH (2012) FunciSNP: an R/bioconductor tool integrating functional non-coding data sets with genetic association studies to identify candidate regulatory SNPs. Nucleic Acids Research 40: e139.

3. DunhamI, KundajeA, AldredSF, CollinsPJ, DavisCA, et al. (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57–74.

4. HoroszewiczJS, LeongSS, KawinskiE, KarrJP, RosenthalH, et al. (1983) LNCaP model of human prostatic carcinoma. Cancer Research 43: 1809–1818.

5. SobelR, SadarM (2005) Cell lines used in prostate cancer research: a compendium of old and new linespart 1. The Journal of Urology 173: 342–359.

6. SobelR, SadarM (2005) Cell lines used in prostate cancer research: a compendium of old and new linespart 2. The Journal of Urology 173: 360–372.

7. JiaL, LandanG, PomerantzM, JaschekR, HermanP, et al. (2009) Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genetics 5: e1000597.

8. PomerantzMM, AhmadiyehN, JiaL, HermanP, VerziMP, et al. (2009) The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nature genetics 41: 882–884.

9. McVeanGA, Altshuler (Co-Chair)DM, Durbin (Co-Chair)RM, AbecasisGR, BentleyDR, et al. (2012) An integrated map of genetic variation from 1,092 human genomes. Nature 491: 56–65.

10. BoyleAP, HongEL, HariharanM, ChengY, SchaubMA, et al. (2012) Annotation of functional variation in personal genomes using RegulomeDB. Genome Research 22: 1790–1797.

11. RhieSK, CoetzeeSG, NoushmehrH, YanC, KimJM, et al. (2013) Comprehensive functional annotation of seventy-one breast cancer risk loci. PLoS ONE 8: e63925.

12. TaplinME (2007) Drug insight: role of the androgen receptor in the development and progression of prostate cancer. Nature Clinical Practice Oncology 4: 236–244.

13. AgalliuI, SuuriniemiM, Prokunina-OlssonL, JohannesonB, CollinsFS, et al. (2008) Evaluation of a Variant in the Transcription Factor 7-Like 2 (tcf7l2) Gene and Prostate Cancer Risk in a Population-Based Study. The Prostate 68: 740–747.

14. ChoiY, SimsGE, MurphyS, MillerJR, ChanAP (2012) Predicting the functional effect of amino acid substitutions and indels. PLoS ONE 7: e46688.

15. KumarP, HenikoffS, NgPC (2009) Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nature protocols 4: 1073–1081.

16. AdzhubeiIA, SchmidtS, PeshkinL, RamenskyVE, GerasimovaA, et al. (2010) A method and server for predicting damaging missense mutations. Nature methods 7: 248–249.

17. BrombergY, RostB (2007) Snap: predict effect of non-synonymous polymorphisms on function. Nucleic Acids Research 35: 3823–3835.

18. FriedmanRC, FarhKKH, BurgeCB, BartelDP (2008) Most mammalian mRNAs are conserved targets of microRNAs. Genome Research 19: 92–105.

19. EelesRA, OlamaAAA, BenllochS, SaundersEJ, LeongamornlertDA, et al. (2013) Identification of 23 new prostate cancer susceptibility loci using the iCOGS custom genotyping array. Nature Genetics 45: 385–391.

20. ZhouL, ZhangX, LiZ, ZhouC, LiM, et al. (2013) Association of a genetic variation in a miR-191 binding site in MDM4 with risk of esophageal squamous cell carcinoma. PLoS ONE 8: e64331.

21. LiuJ, TangX, LiM, LuC, ShiJ, et al. (2013) Functional MDM4 rs4245739 genetic variant, alone and in combination with p53 Arg72Pro polymorphism, contributes to breast cancer susceptibility. Breast Cancer Research and Treatment 140: 151–157.

22. WangJ, ZhuangJ, IyerS, LinX, WhitfieldTW, et al. (2012) Sequence features and chro- matin structure around the genomic regions bound by 119 human transcription factors. Genome Research 22: 1798–1812.

23. HeinzS, BennerC, SpannN, BertolinoE, LinYC, et al. (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and b cell identities. Molecular cell 38: 576–589.

24. YeagerM, OrrN, HayesRB, JacobsKB, KraftP, et al. (2007) Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nature genetics 39: 645–649.

25. GudmundssonJ, SulemP, ManolescuA, AmundadottirLT, GudbjartssonD, et al. (2007) Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nature genetics 39: 631–637.

26. ThomasG, JacobsKB, YeagerM, KraftP, WacholderS, et al. (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nature genetics 40: 310–315.

27. EelesRA, Kote-JaraiZ, GilesGG, OlamaAAA, GuyM, et al. (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nature genetics 40: 316–321.

28. EelesRA, Kote-JaraiZ, Al OlamaAA, GilesGG, GuyM, et al. (2009) Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nature genetics 41: 1116–1121.

29. GudmundssonJ, SulemP, GudbjartssonDF, BlondalT, GylfasonA, et al. (2009) Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nature Genetics 41: 1122–1126.

30. TakataR, AkamatsuS, KuboM, TakahashiA, HosonoN, et al. (2010) Genome-wide association study identifies five new susceptibility loci for prostate cancer in the japanese population. Nature genetics 42: 751–754.

31. WangY, RayAM, JohnsonEK, ZuhlkeKA, CooneyKA, et al. (2011) Evidence for an association between prostate cancer and chromosome 8q24 and 10q11 genetic variants in african american men: The int mens health study. The Prostate 71: 225–231.

32. SchumacherFR, BerndtSI, SiddiqA, JacobsKB, WangZ, et al. (2011) Genome-wide association study identifies new prostate cancer susceptibility loci. Human molecular genetics 20: 3867–3875.

33. Kote-JaraiZ, OlamaAAA, GilesGG, SeveriG, SchleutkerJ, et al. (2011) Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nature Genetics 43: 785–791.

34. GudmundssonJ, SulemP, GudbjartssonDF, MassonG, AgnarssonBA, et al. (2012) A study based on whole-genome sequencing yields a rare variant at 8q24 associated with prostate cancer. Nature Genetics 44: 1326–1329.

35. PorkkaKP, VisakorpiT (2004) Molecular mechanisms of prostate cancer. European urology 45: 683–691.

36. Knudsen BS, Vasioukhin V (2010) Mechanisms of prostate cancer initiation and pro- gression. In: Advances in Cancer Research, Elsevier, volume 109. pp. 1–50. URL http://linkinghub.elsevier.com/retrieve/pii/B9780123808905000016.

37. HuangDW, ShermanBT, LempickiRA (2008) Bioinformatics enrichment tools: paths toward the comprehensive functional analysis of large gene lists. Nucleic Acids Research 37: 1–13.

38. HuangDW, ShermanBT, LempickiRA (2008) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nature Protocols 4: 44–57.

39. GrisanzioC, WernerL, TakedaD, AwoyemiBC, PomerantzMM, et al. (2012) Genetic and functional analyses implicate the NUDT11, HNF1B, and SLC22A3 genes in prostate cancer pathogenesis. Proceedings of the National Academy of Sciences 109: 11252–11257.

40. ShraderTE, CrothersDM (1989) Artificial nucleosome positioning sequences. Proceedings of the National Academy of Sciences 86: 7418–7422.

41. SegalE, Fondufe-MittendorfY, ChenL, ThstrmA, FieldY, et al. (2006) A genomic code for nucleosome positioning. Nature 442: 772–778.

42. ChungHR, VingronM (2009) Sequence-dependent nucleosome positioning. Journal of Molecular Biology 386: 1411–1422.

43. Gutierrez-ArcelusM, LappalainenT, MontgomerySB, BuilA, OngenH, et al. (2013) Passive and active DNA methylation and the interplay with genetic variation in gene regulation. eLife 2: e00523.

44. MauranoMT, HumbertR, RynesE, ThurmanRE, HaugenE, et al. (2012) Systematic localization of common disease-associated variation in regulatory DNA. Science 337: 1190–1195.

45. EwingCM, RayAM, LangeEM, ZuhlkeKA, RobbinsCM, et al. (2012) Germline mu- tations in HOXB13 and prostate-cancer risk. The New England journal of medicine 366: 141–149.

46. International Consortium for Prostate Cancer Genetics (2012) XuJ, LangeEM, LuL, ZhengSL, et al. (2012) HOXB13 is a susceptibility gene for prostate cancer: results from the international consortium for prostate cancer genetics (ICPCG). Human Genetics 132: 5–14.

47. EconomidesKD (2003) Hoxb13 is required for normal differentiation and secretory function of the ventral prostate. Development 130: 2061–2069.

48. JungC (2004) HOXB13 induces growth suppression of prostate cancer cells as a repressor of hormone-activated androgen receptor signaling. Cancer Research 64: 9185–9192.

49. JungC (2004) HOXB13 homeodomain protein suppresses the growth of prostate cancer cells by the negative regulation of t-cell factor 4. Cancer Research 64: 3046–3051.

50. HazelettDJ, CoetzeeSG, CoetzeeGA (2013) A rare variant, which destroys a FoxA1 site at 8q24, is associated with prostate cancer risk. Cell cycle (Georgetown, Tex) 12: 379–380.

51. MarigortaUM, NavarroA (2013) High Trans-ethnic Replicability of GWAS Results Im-plies Common Causal Variants. PLoS Genetics 9: e1003566.

52. LuY, SunJ, KaderAK, KimST, KimJW, et al. (2012) Association of prostate cancer risk with snps in regions containing androgen receptor binding sites captured by ChIP-On-chip analyses. The Prostate 72: 376–385.

53. BermanBP (2002) Exploiting transcription factor binding site clustering to identify cis-regulatory modules involved in pattern formation in the Drosophila genome. Proceedings of the National Academy of Sciences 99: 757–762.

54. JohanssonO, AlkemaW, WassermanWW, LagergrenJ (2003) Identification of functional clusters of transcription factor binding motifs in genome sequences: the MSCAN algorithm. Bioinformatics 19: i169–i176.

55. BermanBP, PfeifferBD, LavertyTR, SalzbergSL, RubinGM, et al. (2004) Computational identification of developmental enhancers: conservation and function of transcription factor binding-site clusters in Drosophila melanogaster and Drosophila pseudoobscura. Genome biology 5: R61.

56. YanJ, EngeM, WhitingtonT, DaveK, LiuJ, et al. (2013) Transcription factor binding in human cells occurs in dense clusters formed around cohesin anchor sites. Cell 154: 801–813.

57. HazelettDJ, LakelandDL, WeissJB (2009) Affinity density: a novel genomic approach to the identification of transcription factor regulatory targets. Bioinformatics (Oxford, England) 25: 1617–1624.

58. DicksonSP, WangK, KrantzI, HakonarsonH, GoldsteinDB (2010) Rare variants create synthetic genome-wide associations. PLoS Biology 8: e1000294.

59. WangK, DicksonSP, StolleCA, KrantzID, GoldsteinDB, et al. (2010) Interpretation of association signals and identification of causal variants from genome-wide association studies. The American Journal of Human Genetics 86: 730–742.

60. FlisterMJ, TsaihSW, O'MearaCC, EndresB, HoffmanMJ, et al. (2013) Identifying multiple causative genes at a single GWAS locus. Genome Research 23: 1996–2002.

61. WangQ, LiW, ZhangY, YuanX, XuK, et al. (2009) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138: 245–256.

62. Prokunina-OlssonL, FuYP, TangW, JacobsKB, HayesRB, et al. (2010) Refining the prostate cancer genetic association within the JAZF1 gene on chromosome 7p15.2. Cancer Epidemiology Biomarkers & Prevention 19: 1349–1355.

63. LiH, LovciMT, KwonYS, RosenfeldMG, FuXD, et al. (2008) Determination of tag density required for digital transcriptome analysis: Application to an androgen-sensitive prostate cancer model. Proceedings of the National Academy of Sciences 105: 20179–20184.

64. DeckerKF, ZhengD, HeY, BowmanT, EdwardsJR, et al. (2012) Persistent androgen receptor-mediated transcription in castration-resistant prostate cancer under androgen-deprived conditions. Nucleic Acids Research 40: 10765–10779.

65. TewariAK, YardimciG, ShibataY, SheffieldNC, SongL, et al. (2012) Chromatin acces-sibility reveals insights into androgen receptor activation and transcriptional specificity. Genome Biology 13: R88.

66. KoontzJI, SorengAL, NucciM, KuoFC, PauwelsP, et al. (2001) Frequent fusion of the JAZF1 and JJAZ1 genes in endometrial stromal tumors. Proceedings of the National Academy of Sciences 98: 6348–6353.

67. MicciF (2006) Consistent rearrangement of chromosomal band 6p21 with generation of fusion genes JAZF1/PHF1 and EPC1/PHF1 in endometrial stromal sarcoma. Cancer Research 66: 107–112.

68. ShembadeN, HarhajNS, LieblDJ, HarhajEW (2007) Essential role for TAX1BP1 in the termination of TNF–α, IL-1- and LPS-mediated NF-κB and JNK signaling. The EMBO Journal 26: 3910–3922.

69. O'GeenH, EchipareL, FarnhamPJ (2011) Using ChIP-Seq technology to generate high-resolution profiles of histone modifications. Methods in Molecular Biology 791: 265–286.

70. LangmeadB, SalzbergS (2012) Fast gapped-read alignment with bowtie 2. Nature Methods 9: 357–359.

71. BlahnikKR, DouL, O'GeenH, McPhillipsT, XuX, et al. (2010) Sole-Search: an inte-grated analysis program for peak detection and functional annotation using ChIP-seq data. Nucleic Acids Research 38: e13.

72. Andreu-VieyraC, LaiJ, BermanBP, FrenkelB, JiaL, et al. (2011) Dynamic nucleosome- depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells. Molecular and Cellular Biology 31: 4648–4662.

73. SharmaN, MassieC, Ramos-MontoyaA, ZecchiniV, ScottH, et al. (2013) The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 23: 35–47.

74. MetropolisN, RosenbluthAW, RosenbluthMN, TellerAH, TellerE (1953) Equation of state calculations by fast computing machines. The Journal of Chemical Physics 21: 1087.

75. HoffmanMD, GelmanA (2012) The no-U-turn sampler: Adaptively setting path lengths in Hamiltonian Monte Carlo. Journal of Machine Learning Research 1–30.

76. Stan Development Team (2013). Stan: A c++ library for probability and sampling, version 1.3. Available: http://mc-stan.org/.

77. GudmundssonJ, SulemP, RafnarT, BergthorssonJT, ManolescuA, et al. (2008) Common sequence variants on 2p15 and xp11.22 confer susceptibility to prostate cancer. Nature Genetics 40: 281–283.

78. MurabitoJM, RosenbergCL, FingerD, KregerBE, LevyD, et al. (2007) A genome-wide association study of breast and prostate cancer in the NHLBI's framingham heart study. BMC medical genetics 8 Suppl 1: S6.

79. XuJ, MoZ, YeD, WangM, LiuF, et al. (2012) Genome-wide association study in chinese men identifies two new prostate cancer risk loci at 9q31.2 and 19q13.4. Nature Genetics 44: 1231–1235.

80. DugganD, ZhengSL, KnowltonM, BenitezD, DimitrovL, et al. (2007) Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. JNCI Journal of the National Cancer Institute 99: 1836–1844.

81. YangL, LiY, LingX, LiuL, LiuB, et al. (2011) A common genetic variant (97906C>A) of DAB2IP/AIP1 is associated with an increased risk and early onset of lung cancer in chinese males. PLoS ONE 6: e26944.

82. NamRK, ZhangW, SiminovitchK, ShlienA, KattanMW, et al. (2011) New variants at 10q26 and 15q21 are associated with aggressive prostate cancer in a genome-wide association study from a prostate biopsy screening cohort. Cancer biology & therapy 12: 997–1004.

83. ZhengSL, StevensVL, WiklundF, IsaacsSD, SunJ, et al. (2009) Two independent prostate cancer risk-associated loci at 11q13. Cancer Epidemiology Biomarkers & Pre-vention 18: 1815–1820.

84. BonillaC, HookerS, MasonT, BockCH, KittlesRA (2011) Prostate cancer susceptibility loci identified on chromosome 12 in african americans. PLoS ONE 6: e16044.

85. GudmundssonJ, SulemP, SteinthorsdottirV, BergthorssonJT, ThorleifssonG, et al. (2007) Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nature genetics 39: 977–983.

86. SunJ, ZhengSL, WiklundF, IsaacsSD, PurcellLD, et al. (2008) Evidence for two independent prostate cancer risk associated loci in the HNF1B gene at 17q12. Nature Genetics 40: 1153–1155.

87. HaimanCA, ChenGK, BlotWJ, StromSS, BerndtSI, et al. (2011) Genome-wide association study of prostate cancer in men of african ancestry identifies a susceptibility locus at 17q21. Nature genetics 43: 570–573.

88. HsuFC, SunJ, WiklundF, IsaacsSD, WileyKE, et al. (2009) A novel prostate cancer susceptibility locus at 19q13. Cancer Research 69: 2720–2723.

89. SunJ, ZhengSL, WiklundF, IsaacsSD, LiG, et al. (2009) Sequence variants at 22q13 are associated with prostate cancer risk. Cancer Research 69: 10–15.