A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk

Lu Y, Beeghly-Fadiel A, Wu L, Guo X, Li B, Schildkraut JM, Im HK, Chen YA, Permuth JB, Reid BM, Teer JK, Moysich KB, Andrulis IL, Anton-Culver H, Arun BK, Bandera EV, Barkardottir RB, Barnes DR, Benitez J, Bjorge L, Brenton J, Butzow R, Caldes T, Caligo MA, Campbell I, Chang-Claude J, Claes KBM, Couch FJ, Cramer D, Daly MB, Defazio A, Dennis J, Diez O, Domchek SM, Doerk T, Easton DF, Eccles DM, Fasching P, Fortner RT, Fountzilas G, Friedman E, Ganz PA, Garber J, Giles GG, Godwin AK, Goldgar DE, Goodman MT, Greene MH, Gronwald J, Hamann U, Heitz F, Hildebrandt MAT, Hogdall CK, Hollestelle A, Hulick PJ, Huntsman DG, Imyanitov EN, Isaacs C, Jakubowska A, James P, Karlan BY, Kelemen LE, Kiemeney LA, Kjaer SK, Kwong A, Le ND, Leslie G, Lesueur F, Levine DA, Mattiello A, May T, Mcguffog L, Mcneish IA, Merritt MA, Modugno F, Montagna M, Neuhausen SL, Nevanlinna H, Nielsen FC, Nikitina-Zake L, Nussbaum RL, Offit K, Olah E, Olopade OI, Olson SH, Olsson H, Osorio A, Park SK, Parsons MT, Peeters PHM, Pejovic T, Peterlongo P, Phelan CM, Pujana MA, Ramus SJ, Rennert G, Risch H, Rodriguez GC, Rodriguez-Antona C, Romieu I, Rookus MA, Rossing MA, Rzepecka IK, Sandler DP, Schmutzler RK, Setiawan VW, Sharma P, Sieh W, Simard J, Singer CF, Song H, Southey MC, Spurdle AB, Sutphen R, Swerdlow AJ, Teixeira MR, Teo SH, Thomassen M, Tischkowitz M, Toland AE, Trichopoulou A, Tung N, Tworoger SS, Van Rensburg EJ, Vanderstichele A, Vega A, Edwards DV, Webb PM, Weitzel JN, Wentzensen N, White E, Wolk A, Wu AH, Yannoukakos D, Zorn KK, Gayther SA, Antoniou AC, Berchuck A, Goode EL, Chenevix-Trench G, Sellers TA, Pharoah PDP, Zheng W, Long J (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Book Volume: 78

Pages Range: 5419-5430

Journal Issue: 18

DOI: 10.1158/0008-5472.CAN-18-0951

Abstract

Large-scale genome-wide association studies (GWAS) have identified approximately 35 loci associated with epithelial ovarian cancer (EOC) risk. The majority of GWAS-identified disease susceptibility variants are located in noncoding regions, and causal genes underlying these associations remain largely unknown. Here, we performed a transcriptome-wide association study to search for novel genetic loci and plausible causal genes at known GWAS loci. We used RNA sequencing data (68 normal ovarian tissue samples from 68 individuals and 6,124 cross-tissue samples from 369 individuals) and high-density genotyping data from European descendants of the Genotype-Tissue Expression (GTEx V6) project to build ovarian and cross-tissue models of genetically regulated expression using elastic net methods. We evaluated 17,121 genes for their cis-predicted gene expression in relation to EOC risk using summary statistics data from GWAS of 97,898 women, including 29,396 EOC cases. With a Bonferroni-corrected significance level of P < 2.2 × 10-6, we identified 35 genes, including FZD4 at 11q14.2 (Z = 5.08, P = 3.83 × 10-7, the cross-tissue model; 1 Mb away from any GWAS-identified EOC risk variant), a potential novel locus for EOC risk. All other 34 significantly associated genes were located within 1 Mb of known GWAS-identified loci, including 23 genes at 6 loci not previously linked to EOC risk. Upon conditioning on nearby known EOC GWAS-identified variants, the associations for 31 genes disappeared and three genes remained (P < 1.47 × 10-3). These data identify one novel locus (FZD4) and 34 genes at 13 known EOC risk loci associated with EOC risk, providing new insights into EOC carcinogenesis.Significance: Transcriptomic analysis of a large cohort confirms earlier GWAS loci and reveals FZD4 as a novel locus associated with EOC risk. Cancer Res; 78(18); 5419-30. ©2018 AACR.

Authors with CRIS profile

Involved external institutions

Vanderbilt University United States (USA) (US) University of Virginia (UVA) United States (USA) (US) University of Chicago United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Roswell Park Cancer Institute United States (USA) (US) Mount Sinai Hospital (MSH) Canada (CA) University of California Irvine United States (USA) (US) University of Texas MD Anderson Cancer Center United States (USA) (US) Rutgers Cancer Institute of New Jersey United States (USA) (US) University of Cambridge United Kingdom (GB) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Helsingin yliopisto / University of Helsinki Finland (FI) Hospital Clínico San Carlos Spain (ES) University of Pisa / Università di Pisa (UniPi) Italy (IT) Peter MacCallum Cancer Centre Australia (AU) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Universiteit Gent (UGent) / Ghent University Belgium (BE) Mayo Clinic United States (USA) (US) University of Sydney (USYD) Australia (AU) Vall d'Hebron University Hospital / Hospital Universitari Vall d'Hebron Spain (ES) University of Pennsylvania United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) University of Southampton United Kingdom (GB) Aristotle University of Thessaloniki Greece (GR) Chaim Sheba Medical Center at Tel HaShomer / המרכז הרפואי עש חיים שיבא – תל השומר‎‎ Israel (IL) University of California Los Angeles (UCLA) United States (USA) (US) Dana–Farber Cancer Institute United States (USA) (US) Cancer Council Victoria Australia (AU) University of Kansas (KU) United States (USA) (US) University of Utah United States (USA) (US) Cedars-Sinai Medical Center United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) HELIOS Kliniken Germany (DE) University of Copenhagen Denmark (DK) Erasmus University Medical Center (MC) Netherlands (NL) NorthShore University HealthSystem United States (USA) (US) University of British Columbia Canada (CA) Petrov Research Institute of Oncology / НИИ Онкологии им. Петрова Russian Federation (RU) Georgetown University United States (USA) (US) The University of Melbourne Australia (AU) Medical University of South Carolina (MUSC) United States (USA) (US) Országos Onkológiai Intézet / National Institute of Oncology Hungary (HU) Memorial Sloan Kettering Cancer Center United States (USA) (US) Lund University / Lunds universitet Sweden (SE) Ciber de Enfermedades Raras (CIBERER) Spain (ES) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Universiteit Utrecht (UU) / Utrecht University Netherlands (NL) Oregon Health and Science University (OSHU) United States (USA) (US) University of New South Wales (UNSW) Australia (AU) Carmel Medical Center Israel (IL) Yale University United States (USA) (US) World Health Organization Switzerland (CH) Netherlands Cancer Institute (NKI) Netherlands (NL) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) National Institute of Environmental Health Sciences United States (USA) (US) Universitätsklinikum Köln Germany (DE) University of Southern California (USC) United States (USA) (US) Icahn School of Medicine at Mount Sinai United States (USA) (US) Brigham and Women's Hospital (BWH) United States (USA) (US) Fox Chase Cancer Center United States (USA) (US) Radboud University Nijmegen Netherlands (NL) Danish Cancer Society Denmark (DK) Hong Kong Hereditary Breast Cancer Registry Hong Kong (HK) British Columbia Cancer Agency Canada (CA) National Institute for Health and Medical Research / Institut national de la santé et de la recherche médicale (INSERM) France (FR) Università degli Studi di Napoli Federico II Italy (IT) University Health Network (UHN) Canada (CA) University of Glasgow United Kingdom (GB) University of Hawaii (U.H.) United States (USA) (US) University of Pittsburgh United States (USA) (US) Istituto di ricovero e cura a carattere scientifico (IRCCS) Italy (IT) Beckman Research Institute of City of Hope (BRI) United States (USA) (US) Copenhagen University Hospital Denmark (DK) Latvian Biomedical Research and Study centre (BMC) / Latvijas Biomedicīnas pētījumu un studiju centrs Latvia (LV) University of California San Francisco (UCSF) United States (USA) (US) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Bellvitge Biomedical Research Institute (IDIBELL) Spain (ES) Fred Hutchinson Cancer Research Center Canada (CA) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) Université Laval (UL) Canada (CA) Medizinische Universität Wien Austria (AT) University of South Florida (USF) United States (USA) (US) The Institute of Cancer Research (ICR) United Kingdom (GB) Instituto Português de Oncologia Francisco Gentil (IPO) / Portuguese Oncology Institute Portugal (PT) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) Odense Universitetshospital (OUH) Denmark (DK) McGill University Canada (CA) Ohio State University United States (USA) (US) National and Kapodistrian University of Athens Greece (GR) Beth Israel Deaconess Medical Center (BIDMC) United States (USA) (US) University of Pretoria South Africa (ZA) University Hospital Leuven (UZ) / Universitaire ziekenhuizen Leuven Belgium (BE) Fundación Pública Galega de Medicina Xenómica Spain (ES) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) City of Hope Medical Center United States (USA) (US) Karolinska Institute Sweden (SE) Duke University United States (USA) (US)

How to cite

APA:

Lu, Y., Beeghly-Fadiel, A., Wu, L., Guo, X., Li, B., Schildkraut, J.M.,... Long, J. (2018). A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk. Cancer Research, 78(18), 5419-5430. https://doi.org/10.1158/0008-5472.CAN-18-0951

MLA:

Lu, Yingchang, et al. "A Transcriptome-Wide Association Study Among 97,898 Women to Identify Candidate Susceptibility Genes for Epithelial Ovarian Cancer Risk." Cancer Research 78.18 (2018): 5419-5430.

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