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


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. SIGNIFICANCE: Mapping the 9p22.2 ovarian cancer risk locus identifies BNC2 as an ovarian cancer risk gene.See related commentary by Choi and Brown, p. 439.

Type Journal
ISBN 1538-7445 (Electronic) 0008-5472 (Linking)
Authors Buckley, M. A.; Woods, N. T.; Tyrer, J. P.; Mendoza-Fandino, G.; Lawrenson, K.; Hazelett, D. J.; Najafabadi, H. S.; Gjyshi, A.; Carvalho, R. S.; Lyra, P. C., Jr.; Coetzee, S. G.; Shen, H. C.; Yang, A. W.; Earp, M. A.; Yoder, S. J.; Risch, H.; Chenevix-Trench, G.; Ramus, S. J.; Phelan, C. M.; Coetzee, G. A.; Noushmehr, H.; Hughes, T. R.; Sellers, T. A.; Goode, E. L.; Pharoah, P. D.; Gayther, S. A.; Monteiro, A. N. A.; Ovarian Cancer Association Consortium.
Published Date 2019-02-01
Published Volume 79
Published Issue 3
Published Pages 467-481
Status Published in-print
DOI 10.1158/0008-5472.CAN-17-3864
URL link to publisher's version