Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Feb 01, 2019
- Source ID
- 10.1158/0008-5472.can-17-3864
Entities
People
- Ally W. Yang
- Alvaro N.a. Monteiro
- Anxhela Gjyshi
- Catherine M. Phelan
- Dennis Hazelett
- Ellen L Goode
- Georgia Chenevix-Trench
- Gustavo Mendoza-fandiño
- Hamed S. Najafabadi
- Harvey A. Risch
- Houtan Noushmehr
- Howard C. Shen
- Jonathan P Tyrer
- Kate Lawrenson
- Madalene A. Earp
- Melissa A. Buckley
- Nicholas T. Woods
- Paul D. Pharoah
- Paulo C. Lyra Jr
- Renato S. Carvalho
- Simon A Gayther
- Simon Coetzee
- Susan J. Ramus
- Thomas A. Sellers
- Timothy R. Hughes
Organizations
- American Cancer Society
- Canadian Institutes of Health Research
- Cedars-Sinai Medical Center
- Garvan Institute of Medical Research
- H. Lee Moffitt Cancer Center & Research Institute
- Henry Ford Health
- Mayo Clinic
- McGill University
- National Cancer Institute
- National Institutes of Health
- Ovarian Cancer Research Alliance
- United States Army Medical Research and Development Command
- University of Cambridge
- University of New South Wales
- University of South Florida
- University of Southern California
- University of Toronto
- Yale School of Public Health