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Cancer Res. 2018 Nov 28. pii: canres.3864.2017. doi: 10.1158/0008-5472.CAN-17-3864. [Epub ahead of print]

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

Author information

1
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute.
2
Eppley Institute for Research in Cancer, University of Nebraska Medical Center.
3
Centre for Cancer Genetic Epidemiology, University of Cambridge.
4
Women's Cancer Program, Cedars-Sinai Medical Center.
5
Biomedical Sciences, Cedars-Sinai Medical Center.
6
Human Genetics, McGill University.
7
Faculdade de Farmácia, Universidade Federal Rural do Rio de Janeiro.
8
University of Southern California.
9
BBDMR, University of Toronto.
10
W21C Research and Innovation Centre, University of Calgary.
11
Molecular Genomics, H. Lee Moffitt Cancer Center.
12
Department of Chronic Disease Epidemiology, Yale School of Public Health.
13
Department of Genetics, QIMR Berghofer Medical Research Institute.
14
School of Women's and Children's Health, University of New South Wales.
15
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute.
16
Van Andel Research Institute, Van Andel Research Institute.
17
Neurosurgery, Henry Ford Health System.
18
University of Toronto.
19
Department of Cancer Epidemiology, Moffitt Cancer Center and Research Institute.
20
Department of Health Sciences Research, Mayo Clinic College of Medicine.
21
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge.
22
Department of Biomedical Sciences, Cedars-Sinai Medical Center.
23
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute alvaro.monteiro@moffitt.org.

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.

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