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Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31

2013; Nature Portfolio; Volume: 4; Issue: 1 Linguagem: Inglês

10.1038/ncomms2613

2041-1723

Jennifer Permuth‐Wey, Kate Lawrenson, Howard C. Shen, Aneliya Velkova, Jonathan P. Tyrer, Zhihua Chen, Hui‐Yi Lin, Y. Ann Chen, Ya-Yu Tsai, Xiaotao Qu, Susan J. Ramus, Rod Karevan, Janet Lee, Nathan Lee, Melissa C. Larson, Katja K.H. Aben, Hoda Anton‐Culver, Natalia Antonenkova, Antonis C. Antoniou, Sebastian M. Armasu, François Bacot, Laura Baglietto, Elisa V. Bandera, Jill S. Barnholtz‐Sloan, Matthias W. Beckmann, Michael J. Birrer, Greg Bloom, Natalia Bogdanova, Louise A. Brinton, Angela Brooks‐Wilson, Robert Brown, Ralf Bützow, Qiuyin Cai, Ian Campbell, Jenny Chang‐Claude, Stephen J. Chanock, Georgia Chenevix‐Trench, Jin Q. Cheng, Mine S. Cicek, Gerhard A. Coetzee, Linda S. Cook, Fergus J. Couch, Daniel W. Cramer, Julie M. Cunningham, Agnieszka Dansonka‐Mieszkowska, Evelyn Despierre, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, Matthias Dürst, Douglas F. Easton, Diana Eccles, Robert P. Edwards, Arif B. Ekici, Peter A. Fasching, David Fenstermacher, James M. Flanagan, Montserrat García‐Closas, Aleksandra Gentry‐Maharaj, Graham G. Giles, Rosalind Glasspool, Jesús González Bosquet, Marc T. Goodman, Martin Gore, Bohdan Górski, Jacek Gronwald, Per Hall, Mari K. Halle, Philipp Harter, Florian Heitz, Peter Hillemanns, Maureen E. Hoatlin, Claus Høgdall, Estrid Høgdall, Satoyo Hosono, Anna Jakubowska, Allan Jensen, Heather Jim, Kimberly R. Kalli, Beth Y. Karlan, Stanley B. Kaye, Linda E. Kelemen, Lambertus A. Kiemeney, Fumitaka Kikkawa, Gottfried E. Konecny, Camilla Krakstad, Susanne K. Kjær, Jolanta Kupryjańczyk, Diether Lambrechts, Sandrina Lambrechts, Johnathan M. Lancaster, Nhu D. Le, Arto Leminen, Douglas A. Levine, Dong Liang, Boon Kiong Lim, Jie Lin, Jolanta Lissowska, Karen H. Lu, Jan Lubiński, Galina Lurie, Leon F.A.G. Massuger, Keitaro Matsuo, Valerie McGuire, Esther M. John, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Toru Nakanishi, Steven A. Narod, Lotte Nedergaard, Roberta B. Ness, Heli Nevanlinna, Stefan Nickels, Houtan Noushmehr, Kunle Odunsi, Sara H. Olson, Irene Orlow, James Paul, Celeste Leigh Pearce, Tanja Pejović, Liisa M. Pelttari, Malcolm C. Pike, Elizabeth M. Poole, Paola Raska, Stefan P. Renner, Harvey A. Risch, Lorna Rodríguez-Rodríguez, Mary Anne Rossing, Anja Rudolph, Ingo B. Runnebaum, Iwona K. Rzepecka, Helga B. Salvesen, Ira Schwaab, Gianluca Severi, Viji Shridhar, Xiao‐Ou Shu, Yurii B. Shvetsov, Weiva Sieh, Honglin Song, Melissa C. Southey, Beata Śpiewankiewicz, Daniel O. Stram, Rebecca Sutphen, Soo‐Hwang Teo, Kathryn L. Terry, Daniel C. Tessier, Pamela J. Thompson, Shelley S. Tworoger, Anne M. van Altena, Ignace Vergote, Robert A. Vierkant, Daniel Vincent, Allison F. Vitonis, Shan Wang‐Gohrke, Rachel Palmieri Weber, Nicolas Wentzensen, Alice S. Whittemore, Elisabeth Wik, Lynne R. Wilkens, Boris Winterhoff, Yin Ling Woo, Anna H. Wu, Yong‐Bing Xiang, Hannah Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Catherine M. Phelan, Edwin S. Iversen, Joellen M. Schildkraut, Andrew Berchuck, Brooke L. Fridley, Ellen L. Goode, Paul D.P. Pharoah, Álvaro N.A. Monteiro, Thomas A. Sellers, Simon A. Gayther,

Cancer-related molecular mechanisms research

Epithelial ovarian cancer (EOC) has a heritable component that remains to be fully characterized. Most identified common susceptibility variants lie in non-protein-coding sequences. We hypothesized that variants in the 3′ untranslated region at putative microRNA (miRNA)-binding sites represent functional targets that influence EOC susceptibility. Here, we evaluate the association between 767 miRNA-related single-nucleotide polymorphisms (miRSNPs) and EOC risk in 18,174 EOC cases and 26,134 controls from 43 studies genotyped through the Collaborative Oncological Gene–environment Study. We identify several miRSNPs associated with invasive serous EOC risk (odds ratio=1.12, P=10−8) mapping to an inversion polymorphism at 17q21.31. Additional genotyping of non-miRSNPs at 17q21.31 reveals stronger signals outside the inversion (P=10−10). Variation at 17q21.31 is associated with neurological diseases, and our collaboration is the first to report an association with EOC susceptibility. An integrated molecular analysis in this region provides evidence for ARHGAP27 and PLEKHM1 as candidate EOC susceptibility genes. Most confirmed susceptibility variants for epithelial ovarian cancer lie in non-protein-coding sequences. Here Permuth-Wey and colleagues investigate variants in 3′ untranslated regions (UTRs) and uncover a new susceptibility locus.