Journal article
Functional analysis and fine mapping of the 9p22.2 ovarian cancer susceptibility locus
MA Buckley, NT Woods, JP Tyrer, G Mendoza-Fandiño, K Lawrenson, DJ Hazelett, HS Najafabadi, A Gjyshi, RS Carvalho, PC Lyra, SG Coetzee, HC Shen, AW Yang, MA Earp, SJ Yoder, H Risch, G Chenevix-Trench, SJ Ramus, CM Phelan, GA Coetzee Show all
Cancer Research | AMER ASSOC CANCER RESEARCH | Published : 2019
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 enric..
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Awarded by Mayo Foundation for Medical Education and Research
Funding Acknowledgements
We thank Alexandra Valle, Jiqiang Yao and Xueli Li for technical assistance and Anindya Dutta for helpful discussions. This work was supported by the following awards: NIH Genetic Association and Mechanisms in Oncology (GAME-ON) through NCI U19 (CA148112, to T.A. Sellers); K99/R00 (CA184415, to K. Lawrenson); and R01 (CA136924, to G.A. Coetzee), a grant from the Ovarian Cancer Research Foundation (258807, to S.A. Gayther), and in part by the Cancer Informatics, Proteomics and the Molecular Genomics Core Facilities at the Moffitt Cancer Center through its NCI CCSG grant (P30-CA76292, to T.A. Sellers). M.A. Buckley is an ARCS (Achievement Rewards for College Scientists) fellow and a recipient of the Ruth L. Kirschstein National Research Service Award (F31 CA165528). Funding of the constituent studies was provided by the American Cancer Society (CRTG-00-196-01-CCE); the California Cancer Research Program (00-01389V-20170, N01-CN25403, 2II0200); the 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; the Cancer Institute of New Jersey; Cancer Research UK (C490/A16561, C490/A6187, C490/A10119, C490/A10124, C536/A13086, C536/A6689); the Celma Mastry Ovarian Cancer Foundation; the Danish Cancer Society (94-222-52); the ELAN Program of the University of Erlangen-Nuremberg; the Eve Appeal; the Helsinki University Hospital Research Fund; Helse Vest; Imperial Experimental Cancer Research Centre (C1312/A15589); the Norwegian Cancer Society; the Norwegian Research Council; the Ovarian Cancer Research Fund; Nationaal Kankerplan of Belgium; Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health Labour and Welfare of Japan; Grants-in-Aid for Scientific Research on Priority Areas and Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, Sports, Culture and Technology of Japan; Takeda Science Foundation; the L&S Milken Foundation; the Polish Ministry of Science and Higher Education (4 PO5C 028 14, 2 PO5A 068 27); Malaysian Ministry of Higher Education (UM.r C/HlR/MOHE/06) and Cancer Research Initiatives Foundation; the Roswell Park Cancer Institute Alliance Foundation; the US National Cancer Institute (K07-CA095666, K07-CA143047, K22-CA138563, 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, R01-CA054419, R01-CA058598, R01-CA058860, R01-CA061107, R01-CA061132, R01-CA063678, R01-CA063682, R01-CA064277, R01-CA067262, R01-CA071766, R01-CA074850, R01-CA076016, R01-CA080742, R01-CA080978, R01-CA083918, R01-CA087538, R01-CA092044, R01-095023, R01-CA106414, R01-CA122443, R01-CA112523, R01-CA114343, R01-CA126841, R01-CA136924, R01-CA149429, R03 CA113148, R03-CA115195, R37-CA070867, R37-CA70867, U01-CA069417, U01-A071966, UM1 CA186107, UM1 CA176726 and Intramural research funds); the 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); the National Health and Medical Research Council of Australia (199600 and 400281); the German Federal Ministry of Education and Research of Germany Programme of Clinical Biomedical Research (01 GB 9401); the German Cancer Research Center (DKFZ); the Minnesota Ovarian Cancer Alliance; the Mayo Foundation; the Fred C. and Katherine B. Andersen Foundation; the Lon V. Smith Foundation (LVS-39420); the Oak Foundation; the OHSU Foundation; the Mermaid I project; the Rudolf-Bartling Foundation; the UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Imperial College London, University College Hospital "Womens Health Theme," the Royal Marsden Hospital; WorkSafeBC, and OvCaRe: British Columbia's Ovarian Cancer Research Team. This study made use of data generated by the Wellcome Trust Case Control consortium; funding for the project was provided by the Wellcome Trust under award 076113.