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

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

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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