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

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. Aben, Hoda Anton-Culver, Natalia Antonenkova, Antonis C. Antoniou, Sebastian M. ArmasuFrançois Bacot, Laura Baglietto, Elisa V. Bandera, Jill Barnholtz-Sloan, Matthias W. Beckmann, Michael J. Birrer, Greg Bloom, Natalia Bogdanova, Louise A. Brinton, Angela Brooks-Wilson, Robert Brown, Ralf Butzow, Qiuyin Cai, Ian Campbell, Jenny Chang-Claude, Stephen 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 Edwards, Arif B. Ekici, Peter A. Fasching, David A. Fenstermacher, James M. Flanagan, Montserrat Garcia-Closas, Aleksandra Gentry-Maharaj, Graham G. Giles, Rosalind M. Glasspool, Jesus Gonzalez-Bosquet, Marc T. Goodman, Martin Gore, Bohdan Górski, Jacek Gronwald, Per Hall, Mari K. Halle, Philipp Harter, Florian Heitz, Peter Hillemanns, Maureen Hoatlin, Claus K. 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 Krüger Kjaer, Jolanta Kupryjanczyk, 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, John R. McLaughlin, 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 L. Pearce, Tanja Pejovic, Liisa M. Pelttari, Malcolm C. Pike, Elizabeth M. Poole, Paola Raska, Stefan P. Renner, Harvey A. Risch, Lorna Rodriguez-Rodriguez, 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 Spiewankiewicz, Daniel 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 P. Yang, Wei Zheng, Argyrios Ziogas, Famida Zulkifli, Catherine M. Phelan, Edwin Iversen, Joellen M. Schildkraut, Andrew Berchuck, Brooke L. Fridley, Ellen L. Goode, Paul D.P. Pharoah, Alvaro N.A. Monteiro, Thomas A. Sellers, Simon A. Gayther

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number1627
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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    Permuth-Wey, J., Lawrenson, K., Shen, H. C., Velkova, A., Tyrer, J. P., Chen, Z., Lin, H. Y., Ann Chen, Y., Tsai, Y. Y., Qu, X., Ramus, S. J., Karevan, R., Lee, J., Lee, N., Larson, M. C., Aben, K. K., Anton-Culver, H., Antonenkova, N., Antoniou, A. C., ... Gayther, S. A. (2013). Identification and molecular characterization of a new ovarian cancer susceptibility locus at 17q21.31. Nature communications, 4, [1627]. https://doi.org/10.1038/ncomms2613