Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus

Melissa A. Buckley, Nicholas T. Woods, Jonathan P. Tyrer, Gustavo Mendoza-Fandiño, Kate Lawrenson, Dennis J. Hazelett, Hamed S. Najafabadi, Anxhela Gjyshi, Renato S. Carvalho, Paulo C. Lyra, Simon G. Coetzee, Howard C. Shen, Ally W. Yang, Madalene A. Earp, Sean J. Yoder, Harvey Risch, Georgia Chenevix-Trench, Susan J. Ramus, Catherine M. Phelan, Gerhard A. CoetzeeHoutan Noushmehr, Timothy R. Hughes, Thomas A. Sellers, Ellen L. Goode, Paul D. Pharoah, Simon A. Gayther, Alvaro N.A. Monteiro, Y. Ann Chen, Brooke L. Fridley, Katja K.H. Aben, Lambertus A. Kiemeney, Hoda Anton-Culver, Argyrios Ziogas, Fiona Bruinsma, Roger L. Milne, Elisa V. Bandera, Graham G. Giles, Yukie T. Bean, Tanja Pejovic, Matthias W. Beckmann, Alexander Hein, Line Bjorge, Peter A. Fasching, Liv C.V. Thomsen, Reidun K. Kopperud, Katharina Bischof, Natalia Bogdanova, Thilo Dörk, Peter Hillemanns, Louise A. Brinton, Nicolas Wentzensen, Hannah Yang, Angela Brooks-Wilson, Clareann H. Bunker, Ralf Butzow, Heli Nevanlinna, Liisa M. Pelttari, Ian G. Campbell, Melissa C. Southey, Francesmary Modugno, Karen Carty, Rosalind Glasspool, Ian McNeish, James Paul, Nadeem Siddiqui, Jenny Chang-Claude, Anja Rudolph, Linda S. Cook, Daniel W. Cramer, Kathryn L. Terry, Julie M. Cunningham, Cezary Cybulski, Jacek Gronwald, Anna Jakubowska, Jan Lubinski, Agnieszka Dansonka-Mieszkowska, Jolanta Kupryjanczyk, Iwona K. Rzepecka, Andreas Du Bois, Philipp Harter, Ed Dicks, Honglin Song, Jennifer A. Doherty, Mary Anne Rossing, Matthias Dürst, Douglas F. Easton, Diana M. Eccles, Robert P. Edwards, Arif B. Ekici, Yu Tang Gao, Aleksandra Gentry-Maharaj, Marc T. Goodman, Pamela J. Thompson, Hanis N. Hasmad, Soo Hwang Teo, Michelle A.T. Hildebrandt, Xifeng Wu, Estrid Hogdall, Allan Jensen, Susanne K. Kjaer, Edwin S. Iversen, Beth Y. Karlan, Jenny Lester, Sandra Orsulic, Christine S. Walsh, Joseph L. Kelley, Diether Lambrechts, Sandrina Lambrechts, Ignace Vergote, Alice W. Lee, Douglas A. Levine, Dong Liang, Jolanta Lissowska, Karen Lu, Lene Lundvall, Leon F.A.G. Massuger, Anne M. Van Altena, Keitaro Matsuo, Valerie McGuire, John R. McLaughlin, Usha Menon, Kirsten B. Moysich, Roberta B. Ness, Kunle Odunsi, Sara H. Olson, Irene Orlow, Malcolm C. Pike, Celeste L. Pearce, Anna H. Wu, Jennifer B. Permuth, Ya Yu Tsai, Shelley S. Tworoger, Elizabeth M. Poole, Barry Rosen, Xiao Ou Shu, Yurii B. Shvetsov, Lynne R. Wilkens, Weiva Sieh, Beata Spiewankiewicz, Lara Sucheston-Campbell, Lotte Thomsen, Shan Wang-Gohrke, Alice S. Whittemore, Yin Ling Woo, Wei Zheng, Andrew Berchuck, Joellen M. Schildkraut, Linda E. Kelemen, Matthew L. Freedman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Genome-wide association studies have identified 40 ovarian cancer risk loci. However, the mechanisms underlying these associations remain elusive. In this study, we conducted a two-pronged approach to identify candidate causal SNPs and assess underlying biological mechanisms at chromosome 9p22.2, the first and most statistically significant associated locus for ovarian cancer susceptibility. Three transcriptional regulatory elements with allele-specific effects and a scaffold/matrix attachment region were characterized and, through physical DNA interactions, BNC2 was established as the most likely target gene. We determined the consensus binding sequence for BNC2 in vitro, verified its enrichment in BNC2 ChIP-seq regions, and validated a set of its downstream target genes. Fine-mapping by dense regional genotyping in over 15,000 ovarian cancer cases and 30,000 controls identified SNPs in the scaffold/matrix attachment region as among the most likely causal variants. This study reveals a comprehensive regulatory landscape at 9p22.2 and proposes a likely mechanism of susceptibility to ovarian cancer.

Original languageEnglish (US)
Pages (from-to)467-481
Number of pages15
JournalCancer Research
Volume79
Issue number3
DOIs
StatePublished - Feb 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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