Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus

Buckley MA, Woods NT, Tyrer JP, Mendoza-Fandino G, Lawrenson K, Hazelett DJ, Najafabadi HS, Gjyshi A, Carvalho RS, Lyra PC, Coetzee SG, Shen HC, Yang AW, Earp MA, Yoder SJ, Risch H, Chenevix-Trench G, Ramus SJ, Phelan CM, Coetzee GA, Noushmehr H, Hughes TR, Sellers TA, Goode EL, Pharoah PD, Gayther SA, Monteiro ANA, Chen YA, Fridley BL, Aben KKH, Kiemeney LA, Anton-Culver H, Ziogas A, Bruinsma F, Milne RL, Bandera EV, Giles GG, Bean YT, Pejovic T, Beckmann M, Hein A, Bjorge L, Fasching PA, Thomsen LCV, Kopperud RK, Bischof K, Bogdanova N, Doek T, Hillemanns P, Brinton LA, Wentzensen N, Yang H, Brooks-Wilson A, Bunker CH, Butzow R, Nevanlinna H, Pelttari LM, Campbell IG, Southey MC, Modugno F, Carty K, Glasspool R, Mcneish I, Paul J, Siddiqui N, Chang-Claude J, Rudolph A, Chang-Claude J, Cook LS, Cramer DW, Terry KL, Cunningham JM, Cybulski C, Gronwald J, Jakubowska A, Lubinski J, Dansonka-Mieszkowska A, Kupryjanczyk J, Rzepecka IK, Du Bois A, Harter P, Dicks E, Song H, Doherty JA, Rossing MA, Duerst M, Easton DF, Eccles DM, Edwards RP, Ekici AB, Fasching P, Gao YT, Milne RL, Gentry-Maharaj A, Giles GG, Goodman MT, Thompson PJ, Hasmad HN, Teo SH, Hildebrandt MAT, Wu X, Hogdall E, Jensen A, Kjaer SK, Hogdall E, Iversen ES, Karlan BY, Lester J, Orsulic S, Walsh CS, Kelley JL, Lambrechts D, Lambrechts S, Vergote I, Lee AW, Levine DA, Liang D, Lissowska J, Lu K, Lundvall L, Kjaer SK, Massuger LFAG, Van Altena AM, Matsuo K, Mcguire V, Mclaughlin JR, Menon U, Moysich KB, Ness RB, Odunsi K, Olson SH, Orlow I, Pike MC, Pearce CL, Wu AH, Permuth JB, Tsai YY, Tworoger SS, Poole EM, Rosen B, Shu XO, Shvetsov YB, Wilkens LR, Sieh W, Spiewankiewicz B, Sucheston-Campbell L, Thomsen L, Wang-Gohrke S, Whittemore AS, Woo YL, Zheng W, Berchuck A, Chenevix-Trench G, Schildkraut JM, Kelemen LE, Freedman ML (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Book Volume: 79

Journal Issue: 3

DOI: 10.1158/0008-5472.CAN-17-3864

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.

Authors with CRIS profile

Involved external institutions

University of New South Wales (UNSW) Australia (AU) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) University of California Irvine United States (USA) (US) University of Toronto Canada (CA) Yale University United States (USA) (US) Cancer Council Victoria Australia (AU) Cedars-Sinai Medical Center United States (USA) (US) Radboud University Nijmegen Netherlands (NL) Stanford University United States (USA) (US) Helsingin yliopisto / University of Helsinki Finland (FI) Ramsay Sime Darby Health Care (RSDHC) Malaysia (MY) Vanderbilt University United States (USA) (US) Mayo Clinic United States (USA) (US) University of Cambridge United Kingdom (GB) California State University (CSUF) United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) Danish Cancer Society Research Center Denmark (DK) Universität Ulm Germany (DE) Duke University United States (USA) (US) University of Malaya (UM) / Universiti Malaya Malaysia (MY) The University of Melbourne Australia (AU) University College London (UCL) United Kingdom (GB) University of Hawaii (U.H.) United States (USA) (US) University of Copenhagen Denmark (DK) Institute for Oncology Ljubljana (OIL) Slovenia (SI) Peter MacCallum Cancer Centre Australia (AU) Oregon Health and Science University (OSHU) United States (USA) (US) Rutgers Cancer Institute of New Jersey United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Kliniken Essen-Mitte Germany (DE) Beatson West of Scotland Cancer Centre (BWSCC) United Kingdom (GB) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Pittsburgh United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Shanghai Cancer Institute / 上海市肿瘤研究所 China (CN) National Cancer Institute (NCI) United States (USA) (US) University of New Mexico (UNM) / Universidad de Nuevo México United States (USA) (US) Friedrich-Schiller-Universität Jena Germany (DE) Brigham and Women's Hospital (BWH) United States (USA) (US) Dartmouth College United States (USA) (US) Princess Anne Hospital United Kingdom (GB) Glasgow Royal Infirmary (GRI) United Kingdom (GB) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Dana–Farber Cancer Institute United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Public Health Ontario Canada (CA) Medical University of South Carolina (MUSC) United States (USA) (US) University of Virginia (UVA) United States (USA) (US) University of Southern California (USC) United States (USA) (US) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Memorial Sloan Kettering Cancer Center United States (USA) (US) Texas Southern University (TSU) United States (USA) (US) Ohio State University United States (USA) (US) Henry Ford Health System (HFHS) United States (USA) (US) Aichi Cancer Center Research Institute Japan (JP) British Columbia Cancer Agency Canada (CA) Icahn School of Medicine at Mount Sinai United States (USA) (US) New York University (NYU) United States (USA) (US) University of Washington United States (USA) (US)

How to cite

APA:

Buckley, M.A., Woods, N.T., Tyrer, J.P., Mendoza-Fandino, G., Lawrenson, K., Hazelett, D.J.,... Freedman, M.L. (2019). Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus. Cancer Research, 79(3). https://doi.org/10.1158/0008-5472.CAN-17-3864

MLA:

Buckley, Melissa A., et al. "Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus." Cancer Research 79.3 (2019).

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