Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer

Hui Shen, Brooke Fridley, Honglin Song, Kate Lawrenson, Julie Cunningham, Susan J Ramus, Mine S Cicek, Jonathan Tyrer, Douglas Stram, Melissa Larson, Martin Kobel, Argyrios Ziogas, Wei Zheng, Hannah P Yang, Anna H Wu, Eva L Wozniak, Yin Ling Woo, Boris Winterhoff, Elizabeth Wik, Alice S WhittemoreNicolas Wentzensen, Rachel Weber, Allison F Vitonis, Daniel Vincent, Robert A Vierkant, Ignace Vergote, David Van Den Berg, Anne M Van Altena, Shelley S Tworoger, Pamela J Thompson, Daniel Tessier, Kathryn L Terry, Soo-Hwang Teo, Claire Templeman, Daniel O Stram, Melissa C Southey, Weiva Sieh, Nadeem Siddiqui, Yurii B Shvetsov, Xiao-Ou Shu, Viji Shridhar, Shan Wang-Gohrke, Gianluca Severi, Ira Schwaab, Helga B Salvesen, Iwona K Rzepecka, Ingo B Runnebaum, Mary Anne Rossing, Lorna Rodriguez-Rodriguez, Harvey A Risch, Stefan P Renner, Elizabeth M Poole, Malcolm C Pike, Catherine M Phelan, Liisa M Pelttari, Tanja Pejovic, James Paul, Irene Orlow, Siti Zawiah Omar, Sara H Olson, Kunle Odunsi, Stefan Nickels, Heli Nevanlinna, Roberta B Ness, Steven A Narod, Toru Nakanishi, Kirsten B Moysich, Alvaro Monteiro, Joanna Moes-Sosnowska, Francesmary Modugno, Usha N Menon, John R McLaughlin, Valerie McGuire, Keitaro Matsuo, Noor A M Adenan, Leon F A G Massuger, Galina Lurie, Lene Lundvall, Jan Lubinski, Jolanta Lissowska, Douglas Levine, Arto Leminen, Alice W Lee, Nhu Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Gottfried E Konecny, Susanne Kruger Kjaer, Lambertus Kiemeney, Linda Kelemen, Gary L Keeney, Beth Karlan, Rod Karevan, Kimberly Kalli, Hiroaki Kajiyama, Bu-tian Ji, Allan Jensen, Anna Jakubowska, Edwin Iversen, Satoyo Hosono, Claus Hogdall, Estrid Hogdall, Maureen Hoatlin, Peter Hillemanns, Florian Heitz, Rebecca Hein, Philipp Harter, Mari Halle, Per Hall, Jacek Gronwald, Martin Gore, Marc T Goodman, Graham Giles, Aleksandra Gentry-Maharaj, Montserrat Garcia-Closas, James Flanagan, Peter Fasching, Arif B Ekici, Robert Edwards, Diana M Eccles, Douglas F Easton, Matthias Duerst, Andreas Du Bois, Thilo Dork, Jennifer Doherty, Evelyn Despierre, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Daniel Cramer, Linda Cook, Xiaoqing Chen, Bridget Charbonneau, Jenny Chang-Claude, Ian G Campbell, Ralf Butzow, Clareann H Bunker, Doerthe Brueggmann, Robert Brown, Angela Brooks-Wilson, Louise Brinton, Natalia Bogdanova, Matthew S Block, Elizabeth Benjamin, Jonathan Beesley, Matthias Beckmann, Elisa Bandera, Laura Baglietto, Francois Bacot, Sebastian Armasu, Natalia Antonenkova, Hoda Anton-Culver, Katja K Aben, Dong Liang, Xifeng Wu, Karen Lu, Michelle A T Hildebrandt, Joellen M Schildkraut, Thomas A Sellers, David Huntsman, Andrew Berchuck, Georgia Chenevix-Trench, Simon A Gayther, Paul D Pharoah, Peter W Laird, Ellen L Goode, Celeste L Pearce

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119 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1 - 10
Number of pages10
JournalNature Communications
Volume4
Issue numberArt # 1628
DOIs
Publication statusPublished - 2013

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