Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions

Dareng EO, Coetzee SG, Tyrer JP, Peng PC, Rosenow W, Chen S, Davis BD, Dezem FS, Seo JH, Nameki R, Reyes AL, Aben KK, Anton-Culver H, Antonenkova NN, Aravantinos G, Bandera EV, Beane Freeman LE, Beckmann M, Beeghly-Fadiel A, Benitez J, Bernardini MQ, Bjorge L, Black A, Bogdanova NV, Bolton KL, Brenton JD, Budzilowska A, Butzow R, Cai H, Campbell I, Cannioto R, Chang-Claude J, Chanock SJ, Chen K, Chenevix-Trench G, Chiew YE, Cook LS, DeFazio A, Dennis J, Doherty JA, Dörk T, du Bois A, Dürst M, Eccles DM, Ene G, Fasching P, Flanagan JM, Fortner RT, Fostira F, Gentry-Maharaj A, Giles GG, Goodman MT, Gronwald J, Haiman CA, Håkansson N, Heitz F, Hildebrandt MA, Høgdall E, Høgdall CK, Huang RY, Jensen A, Jones ME, Kang D, Karlan BY, Karnezis AN, Kelemen LE, Kennedy CJ, Khusnutdinova EK, Kiemeney LA, Kjaer SK, Kupryjanczyk J, Labrie M, Lambrechts D, Larson MC, Le ND, Lester J, Li L, Lubiński J, Lush M, Marks JR, Matsuo K, May T, McLaughlin JR, McNeish IA, Menon U, Missmer S, Modugno F, Moffitt M, Monteiro AN, Moysich KB, Narod SA, Nguyen-Dumont T, Odunsi K, Olsson H, Onland-Moret NC, Park SK, Pejovic T, Permuth JB, Piskorz A, Prokofyeva D, Riggan MJ, Risch HA, Rodríguez-Antona C, Rossing MA, Sandler DP, Setiawan VW, Shan K, Song H, Southey MC, Steed H, Sutphen R, Swerdlow AJ, Teo SH, Terry KL, Thompson PJ, Vestrheim Thomsen LC, Titus L, Trabert B, Travis R, Tworoger SS, Valen E, Van Nieuwenhuysen E, Edwards DV, Vierkant RA, Webb PM, Weinberg CR, Weise RM, Wentzensen N, White E, Winham SJ, Wolk A, Woo YL, Wu AH, Yan L, Yannoukakos D, Zeinomar N, Zheng W, Ziogas A, Berchuck A, Goode EL, Huntsman DG, Pearce CL, Ramus SJ, Sellers TA, Freedman ML, Lawrenson K, Schildkraut JM, Hazelett D, Plummer JT, Kar S, Jones MR, Pharoah PD, Gayther SA (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1016/j.ajhg.2024.04.011

Abstract

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value <5 × 10⁻⁸) and confirmed previously reported associations for 27 risk regions. Conditional analyses identified an additional 11 signals independent of the primary signal at six risk regions (p value <10⁻⁵). Fine mapping identified 4,008 CCVs in these regions, of which 1,452 CCVs were located in ovarian cancer-related chromatin marks with significant enrichment in active enhancers, active promoters, and active regions for CCVs from each EOC histotype. Transcriptome-wide association and colocalization analyses across histotypes using tissue-specific and cross-tissue datasets identified 86 candidate susceptibility genes in known EOC risk regions and 32 genes in 23 additional genomic regions that may represent novel EOC risk loci (false discovery rate <0.05). Finally, by integrating genome-wide HiChIP interactome analysis with transcriptome-wide association study (TWAS), variant effect predictor, transcription factor ChIP-seq, and motifbreakR data, we identified candidate gene-CCV interactions at each locus. This included risk loci where TWAS identified one or more candidate susceptibility genes (e.g., HOXD-AS2, HOXD8, and HOXD3 at 2q31) and other loci where no candidate gene was identified (e.g., MYC and PVT1 at 8q24) by TWAS. In summary, this study describes a functional framework and provides a greater understanding of the biological significance of risk alleles and candidate gene targets at EOC susceptibility loci identified by a genome-wide association study.

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Involved external institutions

University of Cambridge United Kingdom (GB) Cedars-Sinai Medical Center United States (USA) (US) University of Virginia (UVA) United States (USA) (US) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) University of California Irvine United States (USA) (US) N.N. Alexandrov National Cancer Centre of Belarus for Oncology and Medical Radiology Belarus (BY) Agii Anargiri General Oncological Hospital of Kifissia Greece (GR) Rutgers Cancer Institute of New Jersey United States (USA) (US) National Cancer Institute (NCI) United States (USA) (US) Vanderbilt University Medical Center United States (USA) (US) Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) University Health Network (UHN) Canada (CA) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Washington University in St. Louis United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Helsinki University Central Hospital (HUCH) / Helsingin seudun yliopistollinen keskussairaala (HYKS) Finland (FI) Peter MacCallum Cancer Centre Australia (AU) Tianjin Medical University (TMU) / 天津医科大学 China (CN) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) Westmead Institute for Medical Research Australia (AU) University of Colorado Anschutz Medical Campus United States (USA) (US) Katholieke Universiteit Leuven (KUL) / Catholic University of Leuven Belgium (BE) Roswell Park Cancer Institute United States (USA) (US) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Dana–Farber Cancer Institute United States (USA) (US) Huntsman Cancer Institute United States (USA) (US) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Horst-Schmidt-Kliniken Germany (DE) Universitätsklinikum Jena Germany (DE) University of Southampton United Kingdom (GB) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Kræftens Bekæmpelse Denmark (DK) University of California Los Angeles (UCLA) United States (USA) (US) Duke University Health System United States (USA) (US) Aichi Cancer Center Research Institute Japan (JP) Public Health Ontario Canada (CA) Imperial College London / The Imperial College of Science, Technology and Medicine United Kingdom (GB) University College London (UCL) United Kingdom (GB) Brigham and Women's Hospital (BWH) United States (USA) (US) Magee-Womens Foundation United States (USA) (US) H. Lee Moffitt Cancer Center & Research Institute United States (USA) (US) Women's College Hospital Canada (CA) Monash University Australia (AU) University of Chicago United States (USA) (US) Lund University / Lunds universitet Sweden (SE) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) Seoul National University (SNU) / 서울대학교 Korea, Republic of (KR) Oregon Health and Science University (OSHU) United States (USA) (US) National Centre for Scientific Research (NCSR) "Demokritos" Greece (GR) Mayo Clinic United States (USA) (US) University of British Columbia Canada (CA) Keck School of Medicine of USC United States (USA) (US) University of New South Wales (UNSW) Australia (AU) University of Bristol United Kingdom (GB) Cancer Council Victoria Australia (AU) Karolinska Institute Sweden (SE) University of Texas MD Anderson Cancer Center United States (USA) (US) Gentofte Hospital Denmark (DK) Rigshospitalet Denmark (DK) The Institute of Cancer Research (ICR) United Kingdom (GB) UC Davis Medical Center United States (USA) (US) Medical University of South Carolina (MUSC) United States (USA) (US) Russian Academy of Sciences / Росси́йская акаде́мия нау́к (RAS) Russian Federation (RU) Université de Sherbrooke Canada (CA) British Columbia Cancer Agency Canada (CA) Ufa University of Science and Technology (UUST) Russian Federation (RU) Yale University United States (USA) (US) Ciber de Enfermedades Raras (CIBERER) Spain (ES) Fred Hutchinson Cancer Research Center United States (USA) (US) National Institute of Environmental Health Sciences (NIEHS) United States (USA) (US) Hebei Medical University / 河北医科大学 China (CN) University of Alberta Canada (CA) Morsani College of Medicine United States (USA) (US) Cancer Research Initiatives Foundation (CARIF) / Cancer Research Malaysia (CRM) Malaysia (MY) Harvard T.H. Chan School of Public Health United States (USA) (US) University of Southern Maine United States (USA) (US) University of Oxford United Kingdom (GB) Vanderbilt University United States (USA) (US) University of Hawaii (U.H.) United States (USA) (US) University of Washington United States (USA) (US) University of Malaya Medical Centre (UMMC) Malaysia (MY) Emory University United States (USA) (US)

How to cite

APA:

Dareng, E.O., Coetzee, S.G., Tyrer, J.P., Peng, P.C., Rosenow, W., Chen, S.,... Gayther, S.A. (2024). Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions. American Journal of Human Genetics. https://doi.org/10.1016/j.ajhg.2024.04.011

MLA:

Dareng, Eileen O., et al. "Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions." American Journal of Human Genetics (2024).

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