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

Hui Shen, Brooke L. Fridley, Honglin Song, Kate Lawrenson, Julie M. Cunningham, Susan J. Ramus, Mine S. Cicek, Jonathan Tyrer, Douglas Stram, Melissa C. Larson, Martin Köbel, Argyrios Ziogas, Wei Zheng, Hannah P. Yang, Anna H. Wu, Eva L. Wozniak, Yin Ling Woo, Boris Winterhoff, Elisabeth Wik, Alice S. WhittemoreNicolas Wentzensen, Rachel Palmieri 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 C. 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 N.A. Monteiro, Joanna Moes-Sosnowska, Francesmary Modugno, Usha Menon, John R. McLaughlin, Valerie McGuire, Keitaro Matsuo, Noor Azmi Mat Adenan, Leon F.A.G. Massuger, Galina Lurie, Lene Lundvall, Jan Lubiński, Jolanta Lissowska, Douglas A. Levine, Arto Leminen, Alice W. Lee, Nhu D. Le, Sandrina Lambrechts, Diether Lambrechts, Jolanta Kupryjanczyk, Camilla Krakstad, Gottfried E. Konecny, Susanne Krüger Kjaer, Lambertus A. Kiemeney, Linda E. Kelemen, Gary L. Keeney, Beth Y. Karlan, Rod Karevan, Kimberly R. Kalli, Hiroaki Kajiyama, Bu Tian Ji, Allan Jensen, Anna Jakubowska, Edwin Iversen, Satoyo Hosono, Claus K. Høgdall, Estrid Høgdall, Maureen Hoatlin, Peter Hillemanns, Florian Heitz, Rebecca Hein, Philipp Harter, Mari K. Halle, Per Hall, Jacek Gronwald, Martin Gore, Marc T. Goodman, Graham G. Giles, Aleksandra Gentry-Maharaj, Montserrat Garcia-Closas, James M. Flanagan, Peter A. Fasching, Arif B. Ekici, Robert Edwards, Diana Eccles, Douglas F. Easton, Matthias Dürst, Andreas Du Bois, Thilo Dörk, Jennifer A. Doherty, Evelyn Despierre, Agnieszka Dansonka-Mieszkowska, Cezary Cybulski, Daniel W. Cramer, Linda S. Cook, Xiaoqing Chen, Bridget Charbonneau, Jenny Chang-Claude, Ian Campbell, Ralf Butzow, Clareann H. Bunker, Doerthe Brueggmann, Robert Brown, Angela Brooks-Wilson, Louise A. Brinton, Natalia Bogdanova, Matthew S. Block, Elizabeth Benjamin, Jonathan Beesley, Matthias W. Beckmann, Elisa V. Bandera, Laura Baglietto, François Bacot, Sebastian M. 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.P. Pharoah, Peter W. Laird, Ellen L. Goode, Celeste Leigh Pearce

Research output: Contribution to journalArticle

108 Scopus citations

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 (US)
Article number1628
JournalNature communications
Volume4
DOIs
StatePublished - Apr 11 2013

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Shen, H., Fridley, B. L., Song, H., Lawrenson, K., Cunningham, J. M., Ramus, S. J., Cicek, M. S., Tyrer, J., Stram, D., Larson, M. C., Köbel, M., Ziogas, A., Zheng, W., Yang, H. P., Wu, A. H., Wozniak, E. L., Ling Woo, Y., Winterhoff, B., Wik, E., ... Leigh Pearce, C. (2013). Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer. Nature communications, 4, [1628]. https://doi.org/10.1038/ncomms2629