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

Eileen O Dareng, Dareng E, Simon G. Coetzee, Tyrer JP, Jonathan P. Tyrer, Peng PC, Pei-Chen Peng, Rosenow W, Will Rosenow, Chen S, Stephanie Chen, Brian D Davis, Davis BD, Felipe Segato Dezem, Dezem FS, Seo JH, Ji-Heui Seo, Robbin Nameki, Nameki R, Alberto L Reyes, Reyes AL, Aben KKH, Katja K H Aben, Hoda Anton-Culver, Anton-Culver H, Natalia N Antonenkova, Antonenkova NN, Gerasimos Aravantinos, Aravantinos G, Elisa V. Bandera, Bandera EV, Beane Freeman LE, Laura E Beane Freeman, Matthias W. Beckmann, Beckmann MW, Alicia Beeghly-Fadiel, Beeghly-Fadiel A, Javier Benitez, Benitez J, Marcus Q. Bernardini, Bernardini MQ, Bjorge L, Line Bjorge, Amanda Black, Black A, Natalia Bogdanova, Natalia V Bogdanova, Kelly L. Bolton, Bolton KL, Brenton JD, James D. Brenton, Budzilowska A, Agnieszka Budzilowska, Ralf Butzow, Butzow R, Hui Cai, Campbell I, Ian Campbell, Rikki Cannioto, Cannioto R, Chang-Claude J, Jenny Chang-Claude, Chanock SJ, Stephen J Chanock, Kexin Chen, Chen K, Chenevix-Trench G, Georgia Chenevix-Trench, AOCS Group, Chiew YE, Yoke-Eng Chiew, Cook LS, Linda S. Cook, DeFazio A, Anna DeFazio, Dennis J, Joe Dennis, Doherty JA, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, du Bois A, Dürst M, Matthias Dürst, Diana M Eccles, Diana Eccles, Ene G, Gabrielle Ene, Peter A. Fasching, Fasching PA, James M Flanagan, Flanagan JM, Fortner RT, Renée T. Fortner, Florentia Fostira, Fostira F, Aleksandra Gentry-Maharaj, Gentry-Maharaj A, Graham G. Giles, Giles GG, Marc T. Goodman, Goodman M.T., Gronwald J, Jacek Gronwald, Christopher A Haiman, Haiman CA, Niclas Håkansson, Håkansson N, Heitz F, Florian Heitz, Michelle A T Hildebrandt, Hildebrandt MAT, Estrid Høgdall, Høgdall E, Høgdall CK, Claus K Høgdall, Huang RY, Ruea-Yea Huang, Jensen A, Allan Jensen, Michael E. Jones, Jones ME, Kang D, Daehee Kang, Beth Y. Karlan, Karlan BY, Anthony N. Karnezis, Karnezis AN, Kelemen LE, Linda E. Kelemen, Kennedy CJ, Catherine J. Kennedy, Elza K Khusnutdinova, Khusnutdinova EK, Lambertus A. Kiemeney, Kiemeney LA, Kjaer SK, Susanne K Kjaer, Kupryjanczyk J, Jolanta Kupryjanczyk, Labrie M, Marilyne Labrie, Diether Lambrechts, Melissa C. Larson, Larson MC, Nhu D. Le, Le ND, Lester J, Jenny Lester, Lian Li, Li L, Jan Lubiński, Lubiński J, Lush M, Michael Lush, Marks JR, Jeffrey R Marks, Matsuo K, Keitaro Matsuo, May T, Taymaa May, John R. Mclaughlin, McLaughlin JR, Iain A. McNeish, Usha Menon, Missmer S, Stacey Missmer, Modugno F, Francesmary Modugno, Moffitt M, Melissa Moffitt, Monteiro AN, Alvaro N Monteiro, Kirsten B. Moysich, Moysich KB, Steven A. Narod, Narod SA, Tu Nguyen-Dumont, Nguyen-Dumont T, Kunle Odunsi, Odunsi K, Olsson H, Håkan Olsson, Onland-Moret NC, N. Charlotte Onland-Moret, Sue K Park, Park SK, Pejovic T, Tanja Pejovic, Permuth JB, Jennifer B Permuth, Anna Piskorz, Piskorz A, Prokofyeva D, Darya Prokofyeva, Marjorie J Riggan, Riggan MJ, Risch HA, Harvey A. Risch, Rodríguez-Antona C, Cristina Rodríguez-Antona, Mary Anne Rossing, Rossing MA, Dale P. Sandler, Sandler DP, Setiawan VW, V Wendy Setiawan, Shan K, Kang Shan, Honglin Song, Song H, Melissa C. Southey, Southey MC, Helen Steed, Steed H, Sutphen R, Rebecca Sutphen, Anthony J. Swerdlow, Swerdlow AJ, Teo SH, Soo Hwang Teo, Kathryn L. Terry, Pamela J Thompson, Thompson PJ, Vestrheim Thomsen LC, Liv Cecilie Vestrheim Thomsen, Linda Titus, Titus L, Britton Trabert, Ruth Travis, Travis R, Shelley S. Tworoger, Valen E, Ellen Valen, Els Van Nieuwenhuysen, Van Nieuwenhuysen E, Digna Velez Edwards, Edwards DV, Vierkant RA, Robert A. Vierkant, Webb PM, Penelope M. Webb, OPAL study group, Clarice R. Weinberg, Weinberg CR, Weise RM, Rayna Matsuno Weise, Nicolas Wentzensen, Wentzensen N, White E, Emily White, Stacey J. Winham, Winham SJ, Wolk A, Alicja Wolk, Woo YL, Yin-Ling Woo, Wu AH, Anna H. Wu, Li Yan, Yan L, Drakoulis Yannoukakos, Yannoukakos D, Zeinomar N, Nur Zeinomar, Wei Zheng, Ziogas A, Argyrios Ziogas, Andrew Berchuck, Berchuck A, Goode EL, Ellen L. Goode, Huntsman DG, David G. Huntsman, Pearce CL, Celeste L Pearce, Susan J. Ramus, Thomas A. Sellers, Sellers TA, Ovarian Cancer Association Consortium (OCAC), Freedman ML, Matthew L. Freedman, Lawrenson K, Kate Lawrenson, Schildkraut JM, Joellen M. Schildkraut, Hazelett DJ, Dennis Hazelett, Jasmine T Plummer, Plummer JT, Siddhartha Kar, Kar S, Jones MR, Michelle R Jones, Paul D P Pharoah, Gayther SA, Simon A. Gayther
American journal of human genetics · 2024 · vol. 111(6) , pp. 1061–1083 · doi:10.1016/j.ajhg.2024.04.011 · PMID:38723632 · PMC11179261
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This study performed multi-omics analyses of ovarian cancer risk regions, identifying credible causal variants and candidate susceptibility genes, and integrating data to elucidate potential gene-CCV interactions underlying EOC risk.

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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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MeSH descriptors

Genetic Predisposition to Disease Genome-Wide Association Study Ovarian Neoplasms Ovarian Neoplasms Ovarian Neoplasms Polymorphism, Single Nucleotide Carcinoma, Ovarian Epithelial Carcinoma, Ovarian Epithelial Case-Control Studies Female Genomics Genomics Humans Multiomics Risk Factors Transcriptome

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