A Functional Variant at a Prostate Cancer Predisposition Locus at 8q24 Is Associated with Expression

English version České info

Genetic mapping studies have identified multiple cancer susceptibility regions at chromosome 8q24, upstream of the MYC oncogene. MYC has been widely presumed as the regulated target gene, but definitive evidence functionally linking these cancer regions with MYC has been difficult to obtain. Here we examined candidate functional variants of a haplotype block at 8q24 encompassing the two independent risk alleles for prostate and breast cancer, rs620861 and rs13281615. We used the mapping of DNase I hypersensitive sites as a tool to prioritise regions for further functional analysis. This approach identified rs378854, which is in complete linkage disequilibrium (LD) with rs620861, as a novel functional prostate cancer-specific genetic variant. We demonstrate that the risk allele (G) of rs378854 reduces binding of the transcription factor YY1 in vitro. This factor is known to repress global transcription in prostate cancer and is a candidate tumour suppressor. Additional experiments showed that the YY1 binding site is occupied in vivo in prostate cancer, but not breast cancer cells, consistent with the observed cancer-specific effects of this single nucleotide polymorphism (SNP). Using chromatin conformation capture (3C) experiments, we found that the region surrounding rs378854 interacts with the MYC and PVT1 promoters. Moreover, expression of the PVT1 oncogene in normal prostate tissue increased with the presence of the risk allele of rs378854, while expression of MYC was not affected. In conclusion, we identified a new functional prostate cancer risk variant at the 8q24 locus, rs378854 allele G, that reduces binding of the YY1 protein and is associated with increased expression of PVT1 located 0.5 Mb downstream.

Vyšlo v časopise: A Functional Variant at a Prostate Cancer Predisposition Locus at 8q24 Is Associated with Expression. PLoS Genet 7(7): e32767. doi:10.1371/journal.pgen.1002165
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1002165

Souhrn

Zdroje

1. GhoussainiMSongHKoesslerTAl OlamaAAKote-JaraiZ 2008 Multiple loci with different cancer specificities within the 8q24 gene desert. J Natl Cancer Inst 100 962 966

2. EastonDFPooleyKADunningAMPharoahPDThompsonD 2007 Genome-wide association study identifies novel breast cancer susceptibility loci. Nature 447 1087 1093

3. Al OlamaAAKote-JaraiZGilesGGGuyMMorrisonJ 2009 Multiple loci on 8q24 associated with prostate cancer susceptibility. Nat Genet 41 1058 1060

4. KiemeneyLAThorlaciusSSulemPGellerFAbenKK 2008 Sequence variant on 8q24 confers susceptibility to urinary bladder cancer. Nat Genet 40 1307 1312

5. Crowther-SwanepoelDBroderickPDi BernardoMCDobbinsSETorresM 2010 Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat Genet 42 132 136

6. YeagerMChatterjeeNCiampaJJacobsKBGonzalez-BosquetJ 2009 Identification of a new prostate cancer susceptibility locus on chromosome 8q24. Nat Genet 41 1055 1057

7. GudmundssonJSulemPGudbjartssonDFBlondalTGylfasonA 2009 Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat Genet 41 1122 1126

8. LinSDingJ 2009 Integration of ranked lists via cross entropy Monte Carlo with applications to mRNA and microRNA Studies. Biometrics 65 9 18

9. LiuWXieCCZhuYLiTSunJ 2008 Homozygous deletions and recurrent amplifications implicate new genes involved in prostate cancer. Neoplasia 10 897 907

10. GuanYKuoWLStilwellJLTakanoHLapukAV 2007 Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin Cancer Res 13 5745 5755

11. Beck-EngeserGBLumAMHuppiKCaplenNJWangBB 2008 Pvt1-encoded microRNAs in oncogenesis. Retrovirology 5 4

12. AdhikarySEilersM 2005 Transcriptional regulation and transformation by myc proteins. Nature Reviews Molecular Cell Biology 6 635 645

13. HuppiKVolfovskyNRunfolaTJonesTLMackiewiczM 2008 The identification of microRNAs in a genomically unstable region of human chromosome 8q24. Mol Cancer Res 6 212 221

14. PomerantzMMAhmadiyehNJiaLHermanPVerziMP 2009 The 8q24 cancer risk variant rs6983267 shows long-range interaction with MYC in colorectal cancer. Nat Genet 41 882 884

15. TuupanenSTurunenMLehtonenRHallikasOVanharantaS 2009 The common colorectal cancer predisposition SNP rs6983267 at chromosome 8q24 confers potential to enhanced Wnt signaling. Nat Genet 41 885 890

16. WassermanNFAneasINobregaMA 2010 An 8q24 gene desert variant associated with prostate cancer risk confers differential in vivo activity to a MYC enhancer. Genome Res 20 1191 1197

17. JiaLLandanGPomerantzMJaschekRHermanP 2009 Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 5 e1000597 doi:10.1371/journal.pgen.1000597

18. PomerantzMMBeckwithCAReganMMWymanSKPetrovicsG 2009 Evaluation of the 8q24 prostate cancer risk locus and MYC expression. Cancer Res 69 5568 5574

19. Prokunina-OlssonLHallJL 2009 No effect of cancer-associated SNP rs6983267 in the 8q24 region on co-expression of MYC and TCF7L2 in normal colon tissue. Mol Cancer 8 96

20. WrightJBBrownSJColeMD 2010 Upregulation of c-MYC in cis through a large chromatin loop linked to a cancer risk-associated single-nucleotide polymorphism in colorectal cancer cells. Mol Cell Biol 30 1411 1420

21. BoyleAPDavisSShulhaHPMeltzerPMarguliesEH 2008 High-resolution mapping and characterization of open chromatin across the genome. Cell 132 311 322

22. UdlerMSMeyerKBPooleyKAKarlinsEStruewingJP 2009 FGFR2 variants and breast cancer risk: fine-scale mapping using African American studies and analysis of chromatin conformation. Hum Mol Genet 18 1692 1703

23. UdlerMSAhmedSHealeyCSMeyerKStruewingJ 2010 Fine scale mapping of the breast cancer 16q12 locus. Hum Mol Genet 19 2507 2515

24. SchmidtDSchwaliePCRoss-InnesCSHurtadoABrownGD 2010 A CTCF-independent role for cohesin in tissue-specific transcription. Genome Res 20 578 588

25. TurnbullCAhmedSMorrisonJPernetDRenwickA 2010 Genome-wide association study identifies five new breast cancer susceptibility loci. (2010). Nat Genet 42 504 507

26. ThomasMJSetoE 1999 Unlocking the mechanisms of transcription factor YY1: are chromatin modifying enzymes the key? Gene 236 197 208

27. BreslinMBVedeckisWV 1998 The human glucocorticoid receptor promoter upstream sequences contain binding sites for the ubiquitous transcription factor, Yin Yang 1. J Steroid Biochem Mol Biol 67 369 381

28. GordonSAkopyanGGarbanHBonavidaB 2006 Transcription factor YY1: structure, function, and therapeutic implications in cancer biology. Oncogene 25 1125 1142

29. AhmadiyehNPomerantzMMGrisanzioCHermanPJiaL 2010 8q24 prostate, breast, and colon cancer risk loci show tissue-specific long-range interaction with MYC. Proc Natl Acad Sci U S A 107 9742 9746

30. SeligsonDHorvathSHuerta-YepezSHannaSGarbanH 2005 Expression of transcription factor Yin Yang 1 in prostate cancer. Int J Oncol 27 131 141

31. HurtadoAHolmesKARoss-InnesCSSchmidtDCarrollJS 2011 FOXA1 is a key determinant of estrogen receptor function and endocrine response. Nat Genet 43 11 12

32. AskerCMareniCCovielloDIngvarssonSSessaregoM 1988 Amplification of c-myc and pvt-1 homologous sequences in acute nonlymphatic leukemia. Leuk Res 12 523 527

33. BakkusMHBrakel-van PeerKMMichielsJJvan 't VeerMBBennerR 1990 Amplification of the c-myc and the pvt-like region in human multiple myeloma. Oncogene 5 1359 1364

34. GrahamMAdamsJM 1986 Chromosome 8 breakpoint far 3′ of the c-myc oncogene in a Burkitt's lymphoma 2;8 variant translocation is equivalent to the murine pvt-1 locus. EMBO J 5 2845 2851

35. CarramusaLContinoFFerroAMinafraLPercontiG 2007 The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. J Cell Physiol 213 511 518

36. Enciso-MoraVBroderickPMaYJarrettRFHjalgrimH 2010 A genome-wide association study of Hodgkin's lymphoma identifies new susceptibility loci at 2p16.1 (REL), 8q24.21 and 10p14 (GATA3). Nat Genet 42 1126 1130

37. LiHDurbinR 2009 Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25 1754 1760

38. DekkerJRippeKDekkerMKlecknerN 2002 Capturing chromosome conformation. Science 295 1306 1311

39. WestAGFraserP 2005 Remote control of gene transcription. Hum Mol Genet 14 Spec No 1 R101 111

40. MeyerKBMaiaATO'ReillyMTeschendorffAEChinSF 2008 Allele-specific up-regulation of FGFR2 increases susceptibility to breast cancer. PLoS Biol 6 e108 doi:10.1371/journal.pbio.0060108

41. SchmidtDWilsonMDSpyrouCBrownGDHadfieldJ 2009 ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions. Methods 48 240 248

42. KimJKollhoffABergmannAStubbsL 2003 Methylation-sensitive binding of transcription factor YY1 to an insulator sequence within the paternally expressed imprinted gene, Peg3. Hum Mol Genet 12 233 245