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, on behalf of the Ovarian Cancer Association Consortium

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3 Citations (Scopus)

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
Pages (from-to)467-481
Number of pages15
JournalCancer Research
Volume79
Issue number3
DOIs
Publication statusPublished - 1 Feb 2019
Externally publishedYes

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