期刊
CANCER RESEARCH
卷 79, 期 3, 页码 467-481出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-17-3864
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资金
- NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI [CA148112, CA184415, CA136924]
- Ovarian Cancer Research Foundation [258807]
- Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant [P30-CA76292]
- Ruth L. Kirschstein National Research Service Award [F31 CA165528]
- American Cancer Society [CRTG-00-196-01-CCE]
- California Cancer Research Program [00-01389V-20170, N01-CN25403, 2II0200]
- Canadian Institutes for Health Research [MOP-86727]
- Cancer Council Victoria
- Cancer Council Queensland
- Cancer Council New South Wales
- Cancer Council South Australia
- Cancer Council Tasmania
- Cancer Foundation of Western Australia
- Cancer Institute of New Jersey
- Cancer Research UK [C490/A16561, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689]
- Celma Mastry Ovarian Cancer Foundation
- Danish Cancer Society [94-222-52]
- ELAN Program of the University of Erlangen-Nuremberg
- Eve Appeal
- Helsinki University Hospital Research Fund
- Helse Vest
- Imperial Experimental Cancer Research Centre [C1312/A15589]
- Norwegian Cancer Society
- Norwegian Research Council
- Ovarian Cancer Research Fund
- Nationaal Kankerplan of Belgium
- Ministry of Health Labour and Welfare of Japan
- Ministry of Education, Science, Sports, Culture and Technology of Japan
- Takeda Science Foundation
- L&S Milken Foundation
- Polish Ministry of Science and Higher Education [4 PO5C 028 14, 2 PO5A 068 27]
- Malaysian Ministry of Higher Education [UM.C/HlR/MOHE/06]
- Cancer Research Initiatives Foundation
- Roswell Park Cancer Institute Alliance Foundation
- US National Cancer Institute [K07-CA095666, K07-CA143047, K22-CA138563, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R37-CA070867, R37-CA70867, U01-CA069417, U01-A071966, UM1 CA186107, UM1 CA176726]
- US Army Medical Research and Material Command [DAMD17-98-1-8659, DAMD17-01-1-0729, DAMD17-02-1-0666, DAMD17-02-1-0669, W81XWH-10-1-0280, W81XWH-07-0449, W81XWH-10-1-02802]
- National Health and Medical Research Council of Australia [199600, 400281]
- German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research [01 GB 9401]
- German Cancer Research Center (DKFZ)
- Minnesota Ovarian Cancer Alliance
- Mayo Foundation
- Fred C. and Katherine B. Andersen Foundation
- Lon V. Smith Foundation [LVS-39420]
- Oak Foundation
- OHSU Foundation
- Mermaid I project
- Rudolf-Bartling Foundation
- UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge
- Imperial College London
- University College Hospital Womens Health Theme
- Royal Marsden Hospital
- WorkSafeBC
- OvCaRe: British Columbia's Ovarian Cancer Research Team
- Wellcome Trust [076113]
- [N01-CN55424]
- [N01-PC067010]
- [N01-PC035137]
- [P01-CA017054]
- [P01-CA087696]
- [P01-CA87969]
- [P30-CA15083]
- [P50-CA105009]
- [P50-CA136393]
- [P50-CA159981]
- [R01-CA014089]
- [R01-CA016056]
- [R01-CA017054]
- [R01-CA049449]
- [R01-CA050385]
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.
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