The EPIC-Norfolk Study
Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer.
Nature communications 2012 ; 4: 1628.
Shen H, Fridley BL, Song H, Lawrenson K, Cunningham JM, Ramus SJ, Cicek MS, Tyrer J, Stram D, Larson MC, Köbel M, PRACTICAL Consortium, Ziogas A, Zheng W, Yang HP, Wu AH, Wozniak EL, Woo YL, Winterhoff B, Wik E, Whittemore AS, Wentzensen N, Weber RP, Vitonis AF, Vincent D, Vierkant RA, Vergote I, Van Den Berg D, Van Altena AM, Tworoger SS, Thompson PJ, Tessier DC, Terry KL, Teo SH, Templeman C, Stram DO, Southey MC, Sieh W, Siddiqui N, Shvetsov YB, Shu XO, Shridhar V, Wang-Gohrke S, Severi G, Schwaab I, Salvesen HB, Rzepecka IK, Runnebaum IB, Rossing MA, Rodriguez-Rodriguez L, Risch HA, Renner SP, Poole EM, Pike MC, Phelan CM, Pelttari LM, Pejovic T, Paul J, Orlow I, Omar SZ, Olson SH, Odunsi K, Nickels S, Nevanlinna H, Ness RB, Narod SA, Nakanishi T, Moysich KB, Monteiro AN, Moes-Sosnowska J, Modugno F, Menon U, McLaughlin JR, McGuire V, Matsuo K, Adenan NA, Massuger LF, Lurie G, Lundvall L, Lubinski J, Lissowska J, Levine DA, Leminen A, Lee AW, Le ND, Lambrechts S, Lambrechts D, Kupryjanczyk J, Krakstad C, Konecny GE, Kjaer SK, Kiemeney LA, Kelemen LE, Keeney GL, Karlan BY, Karevan R, Kalli KR, Kajiyama H, Ji BT, Jensen A, Jakubowska A, Iversen E, Hosono S, Høgdall CK, Høgdall E, Hoatlin M, Hillemanns P, Heitz F, Hein R, Harter P, Halle MK, Hall P, Gronwald J, Gore M, Goodman MT, Giles GG, Gentry-Maharaj A, García-Closas M, Flanagan JM, Fasching PA, Ekici AB, Edwards R, Eccles D, Easton DF, Dürst M, du Bois A, Dörk T, Doherty JA, Despierre E, Dansonka-Mieszkowska A, Cybulski C, Cramer DW, Cook LS, Chen X, Charbonneau B, Chang-Claude J, Campbell I, Butzow R, Bunker CH, Brueggmann D, Brown R, Brooks-Wilson A, Brinton LA, Bogdanova N, Block MS, Benjamin E, Beesley J, Beckmann MW, Bandera EV, Baglietto L, Bacot F, Armasu SM, Antonenkova N, Anton-Culver H, Aben KK, Liang D, Wu X, Lu K, Hildebrandt MA, Australian Ovarian Cancer Study Group, Australian Cancer Study, Schildkraut JM, Sellers TA, Huntsman D, Berchuck A, Chenevix-Trench G, Gayther SA, Pharoah PD, Laird PW, Goode EL, and Pearce CL
DOI : 10.1038/ncomms2629
PubMed ID : 23535649
PMCID : PMC3848248
URL : https://www.nature.com/articles/ncomms2629
Abstract
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR)=1.13, P=3.1 × 10(-10)) and clear cell (rs11651755 OR=0.77, P=1.6 × 10(-8)) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.