GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Paul D P Pharoah, Ya Yu Tsai, Susan J. Ramus, Catherine M. Phelan, Ellen L. Goode, Kate Lawrenson, Melissa Buckley, Brooke L. Fridley, Jonathan P. Tyrer, Howard Shen, Rachel Weber, Rod Karevan, Melissa C. Larson, Honglin Song, Daniel C. Tessier, François Bacot, Daniel Vincent, Julie M. Cunningham, Joe Dennis, Ed DicksKatja K. Aben, Hoda Anton-Culver, Natalia Antonenkova, Sebastian M. Armasu, Laura Baglietto, Elisa V. Bandera, Matthias W. Beckmann, Michael J. Birrer, Greg Bloom, Natalia Bogdanova, James D. Brenton, Louise A. Brinton, Angela Brooks-Wilson, Robert Brown, Ralf Butzow, Ian Campbell, Michael E. Carney, Renato S. Carvalho, Jenny Chang-Claude, Y. Anne Chen, Zhihua Chen, Wong Ho Chow, Mine S. Cicek, Gerhard Coetzee, Linda S. Cook, Daniel W. Cramer, Cezary Cybulski, Agnieszka Dansonka-Mieszkowska, Evelyn Despierre, Jennifer A. Doherty, Thilo Dörk, Andreas Du Bois, Matthias Dürst, Diana Eccles, Robert Edwards, Arif B. Ekici, Peter A. Fasching, David Fenstermacher, James Flanagan, Yu Tang Gao, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Graham Giles, Anxhela Gjyshi, Martin Gore, Jacek Gronwald, Qi Guo, Mari K. Halle, Philipp Harter, Alexander Hein, Florian Heitz, Peter Hillemanns, Maureen Hoatlin, Estrid Høgdall, Claus K. Høgdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Kimberly R. Kalli, Beth Y. Karlan, Linda E. Kelemen, Lambertus A. Kiemeney, Susanne Krüger Kjaer, Gottfried E. Konecny, Camilla Krakstad, Jolanta Kupryjanczyk, Diether Lambrechts, Sandrina Lambrechts, Nhu D. Le, Nathan Lee, Janet Lee, Arto Leminen, Boon Kiong Lim, Jolanta Lissowska, Jan Lubiński, Lene Lundvall, Galina Lurie, Leon F A G Massuger, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Toru Nakanishi, Steven A. Narod, Roberta B. Ness, Heli Nevanlinna, Stefan Nickels, Houtan Noushmehr, Kunle Odunsi, Sara Olson, Irene Orlow, James Paul, Tanja Pejovic, Liisa M. Pelttari, Jenny Permuth-Wey, Malcolm C. Pike, Elizabeth M. Poole, Xiaotao Qu, Harvey A. Risch, Lorna Rodriguez-Rodriguez, Mary Anne Rossing, Anja Rudolph, Ingo Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Ira Schwaab, Gianluca Severi, Hui Shen, Vijayalakshmi Shridhar, Xiao Ou Shu, Weiva Sieh, Melissa C. Southey, Paul Spellman, Kazuo Tajima, Soo Hwang Teo, Kathryn L. Terry, Pamela J. Thompson, Agnieszka Timorek, Shelley S. Tworoger, Anne M. Van Altena, David Van Den Berg, Ignace Vergote, Robert A. Vierkant, Allison F. Vitonis, Shan Wang-Gohrke, Nicolas Wentzensen, Alice S. Whittemore, Elisabeth Wik, Boris Winterhoff, Yin Ling Woo, Anna H. Wu, Hannah P. Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Marc T. Goodman, Per Hall, Douglas F. Easton, Celeste L. Pearce, Andrew Berchuck, Georgia Chenevix-Trench, Edwin Iversen, Alvaro N A Monteiro, Simon A. Gayther, Joellen M. Schildkraut, Thomas A. Sellers

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Abstract

Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10-9) and 10p12 (rs1243180, P = 1.8 × 10-8) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10-10). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.

Original languageEnglish (US)
Pages (from-to)362-370
Number of pages9
JournalNature Genetics
Volume45
Issue number4
DOIs
StatePublished - Apr 2013

Bibliographical note

Funding Information:
We thank all the individuals who took part in this study and all the researchers, clinicians and technical and administrative staff who made possible the many studies contributing to this work (a full list is provided in the Supplementary Note). The COGS project is funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009-223175). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were supported in part by the Genetic Associations and Mechanisms in Oncology (GAME-ON) and a National Cancer Institute Cancer Post-GWAS Initiative (U19-CA148112). Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113. A full list of the investigators who contributed to the generation of the data is available from the website (see URLs). The results published here are based in part on data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute; information about The Cancer Genome Atlas (TCGA) and the investigators and institutions who constitute the TCGA research network can be found on the website (see URLs).

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