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

Melissa A Buckley; Nicholas T Woods; Jonathan P Tyrer; Gustavo Mendoza-Fandiño; Kate Lawrenson; Dennis J Hazelett; Hamed S Najafabadi; Anxhela Gjyshi; Renato S Carvalho; Paulo C Lyra, Jr; Simon G Coetzee; Howard C Shen; Ally W Yang; Madalene A Earp; Sean J Yoder; Harvey Risch; Georgia Chenevix-Trench; Susan J Ramus; Catherine M Phelan; Gerhard A Coetzee; Houtan Noushmehr; Timothy R Hughes; Thomas A Sellers; Ellen L Goode; Paul D Pharoah; Simon A Gayther; Alvaro N A Monteiro; Elisa Bandera; Ovarian Cancer Association Consortium

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

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

Journal article

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

Melissa A Buckley, Nicholas T Woods, Jonathan P Tyrer, Gustavo Mendoza-Fandiño, Kate Lawrenson, Dennis J Hazelett, Hamed S Najafabadi, Anxhela Gjyshi, Renato S Carvalho, Paulo C Lyra, Jr, …

Cancer research (Chicago, Ill.), Vol.79(3), pp.467-481

02/01/2019

DOI: https://doi.org/10.1158/0008-5472.CAN-17-3864

PMCID: PMC6359979

PMID: 30487138

Abstract

Base Sequence

Carcinoma, Ovarian Epithelial - genetics

Cell Cycle Proteins - genetics

Cell Line, Tumor

Chromosome Mapping

Chromosomes, Human, Pair 9

Cystadenocarcinoma, Serous - genetics

DNA, Neoplasm - genetics

DNA-Binding Proteins - genetics

Female

Genetic Predisposition to Disease

Genome-Wide Association Study

HEK293 Cells

Humans

Linkage Disequilibrium

Ovarian Neoplasms - genetics

Polymorphism, Single Nucleotide

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, was established as the most likely target gene. We determined the consensus binding sequence for BNC2 , 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 as an ovarian cancer risk gene. .

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Title: Functional Analysis and Fine Mapping of the 9p22.2 Ovarian Cancer Susceptibility Locus
Creators: Melissa A Buckley - University of South Florida Cancer Biology PhD Program, Tampa, Florida
Nicholas T Woods - Department of Oncological Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida
Jonathan P Tyrer - The Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Gustavo Mendoza-Fandiño - Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Kate Lawrenson - Women's Cancer Program at the Samuel Oschin Comprehensive, Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Dennis J Hazelett - Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
Hamed S Najafabadi - Department of Human Genetics, McGill University, Montreal, Quebec, Canada
Anxhela Gjyshi - University of South Florida Cancer Biology PhD Program, Tampa, Florida
Renato S Carvalho - Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Paulo C Lyra, Jr - Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Simon G Coetzee - Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California
Howard C Shen - Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer Center, Los Angeles, California
Ally W Yang - Donnelly Centre, University of Toronto, Toronto, Ontario, Canada
Madalene A Earp - Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, Minnesota
Sean J Yoder - Molecular Genomics Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Harvey Risch - Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut
Georgia Chenevix-Trench - QIMR Berghofer Medical Research Institute, Brisbane, Australia
Susan J Ramus - The Kinghorn Cancer Center, Garvan Institute of Medical Research, Darlinghurst, Australia
Catherine M Phelan - Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Gerhard A Coetzee - Van Andel Institute, Grand Rapids, Michigan
Houtan Noushmehr - Department of Neurosurgery, Henry Ford Health System, Detroit, Michigan
Timothy R Hughes - Canadian Institutes for Advanced Research, Toronto, Ontario, Canada
Thomas A Sellers - Cancer Epidemiology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
Ellen L Goode - Division of Biomedical Statistics and Informatics, Department of Health Science Research, Mayo Clinic, Rochester, Minnesota
Paul D Pharoah - The Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
Simon A Gayther - Center for Bioinformatics and Functional Genomics, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
Alvaro N A Monteiro
Elisa Bandera - Rutgers University, Cancer Epidemiology and Health Outcomes
Ovarian Cancer Association Consortium
Publication Details: Cancer research (Chicago, Ill.), Vol.79(3), pp.467-481
Date published: 02/01/2019
Grant note: R03 CA113148 / NCI NIH HHS N01 CN025403 / NCI NIH HHS Department of Health R37 CA070867 / NCI NIH HHS K22 CA138563 / NCI NIH HHS R00 CA184415 / NCI NIH HHS 10119 / Cancer Research UK R03 CA115195 / NCI NIH HHS U01 CA069417 / NCI NIH HHS R01 CA063682 / NCI NIH HHS R01 CA058598 / NCI NIH HHS P01 CA017054 / NCI NIH HHS R01 CA067262 / NCI NIH HHS R01 CA080742 / NCI NIH HHS P50 CA105009 / NCI NIH HHS R01 CA083918 / NCI NIH HHS R01 CA074850 / NCI NIH HHS R01 CA054419 / NCI NIH HHS R01 CA064277 / NCI NIH HHS R01 CA136924 / NCI NIH HHS R01 CA076016 / NCI NIH HHS K07 CA092044 / NCI NIH HHS P01 CA087969 / NCI NIH HHS K07 CA143047 / NCI NIH HHS P30 CA016056 / NCI NIH HHS C536/A6689 / Cancer Research UK MOP-86727 / CIHR 076113 / Wellcome Trust R01 CA087538 / NCI NIH HHS C490/A16561 / Cancer Research UK R01 CA122443 / NCI NIH HHS U54 CA163068 / NCI NIH HHS C1312/A15589 / Cancer Research UK Wellcome Trust R01 CA058860 / NCI NIH HHS F31 CA165528 / NCI NIH HHS U54 CA163071 / NCI NIH HHS UM1 CA176726 / NCI NIH HHS R01 CA063678 / NCI NIH HHS P30 CA015083 / NCI NIH HHS K07 CA095666 / NCI NIH HHS R01 CA106414 / NCI NIH HHS N01PC35137 / NCI NIH HHS R01 CA112523 / NCI NIH HHS R01 CA149429 / NCI NIH HHS R01 CA114343 / NCI NIH HHS K99 CA184415 / NCI NIH HHS 10124 / Cancer Research UK R01 CA087696 / NCI NIH HHS U19 CA148112 / NCI NIH HHS P50 CA159981 / NCI NIH HHS C490/A6187 / Cancer Research UK P20 GM121316 / NIGMS NIH HHS P30 CA076292 / NCI NIH HHS N01 PC067010 / NCI NIH HHS R01 CA050385 / NCI NIH HHS P30 CA008748 / NCI NIH HHS R01 CA092309 / NCI NIH HHS UM1 CA186107 / NCI NIH HHS C536/A13086 / Cancer Research UK P50 CA136393 / NCI NIH HHS R01 CA049449 / NCI NIH HHS R01 CA126841 / NCI NIH HHS P30 CA014089 / NCI NIH HHS
Academic Unit: Cancer Epidemiology and Health Outcomes
Language: English
Resource Type: Journal article
Identifiers: 991031666005104646