Journal Article

DKFZ-2024-00995

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

Dareng, E. O. ; Coetzee, S. G. ; Tyrer, J. P. ; Peng, P.-C. ; Rosenow, W. ; Chen, S. ; Davis, B. D. ; Dezem, F. S. ; Seo, J.-H. ; Nameki, R. ; Reyes, A. L. ; Aben, K. K. H. ; Anton-Culver, H. ; Antonenkova, N. N. ; Aravantinos, G. ; Bandera, E. V. ; Beane Freeman, L. E. ; Beckmann, M. W. ; Beeghly-Fadiel, A. ; Benitez, J. ; Bernardini, M. Q. ; Bjorge, L. ; Black, A. ; Bogdanova, N. V. ; Bolton, K. L. ; Brenton, J. D. ; Budzilowska, A. ; Butzow, R. ; Cai, H. ; Campbell, I. ; Cannioto, R. ; Chang-Claude, J.DKFZ* ; Chanock, S. J. ; Chen, K. ; Chenevix-Trench, G. ; Group, A. (Collaboration Author) ; Chiew, Y.-E. ; Cook, L. S. ; DeFazio, A. ; Dennis, J. ; Doherty, J. A. ; Dörk, T. ; du Bois, A. ; Dürst, M. ; Eccles, D. M. ; Ene, G. ; Fasching, P. A. ; Flanagan, J. M. ; Fortner, R. T.DKFZ* ; Fostira, F. ; Gentry-Maharaj, A. ; Giles, G. G. ; Goodman, M. T. ; Gronwald, J. ; Haiman, C. A. ; Håkansson, N. ; Heitz, F. ; Hildebrandt, M. A. T. ; Høgdall, E. ; Høgdall, C. K. ; Huang, R.-Y. ; Jensen, A. ; Jones, M. E. ; Kang, D. ; Karlan, B. Y. ; Karnezis, A. N. ; Kelemen, L. E. ; Kennedy, C. J. ; Khusnutdinova, E. K. ; Kiemeney, L. A. ; Kjaer, S. K. ; Kupryjanczyk, J. ; Labrie, M. ; Lambrechts, D. ; Larson, M. C. ; Le, N. D. ; Lester, J. ; Li, L. ; Lubiński, J. ; Lush, M. ; Marks, J. R. ; Matsuo, K. ; May, T. ; McLaughlin, J. R. ; McNeish, I. A. ; Menon, U. ; Missmer, S. ; Modugno, F. ; Moffitt, M. ; Monteiro, A. N. ; Moysich, K. B. ; Narod, S. A. ; Nguyen-Dumont, T. ; Odunsi, K. ; Olsson, H. ; Onland-Moret, N. C. ; Park, S. K. ; Pejovic, T. ; Permuth, J. B. ; Piskorz, A. ; Prokofyeva, D. ; Riggan, M. J. ; Risch, H. A. ; Rodríguez-Antona, C. ; Rossing, M. A. ; Sandler, D. P. ; Setiawan, V. W. ; Shan, K. ; Song, H. ; Southey, M. C. ; Steed, H. ; Sutphen, R. ; Swerdlow, A. J. ; Teo, S. H. ; Terry, K. L. ; Thompson, P. J. ; Vestrheim Thomsen, L. C. ; Titus, L. ; Trabert, B. ; Travis, R. ; Tworoger, S. S. ; Valen, E. ; Van Nieuwenhuysen, E. ; Edwards, D. V. ; Vierkant, R. A. ; Webb, P. M. ; Group, O. S. (Collaboration Author) ; Weinberg, C. R. ; Weise, R. M. ; Wentzensen, N. ; White, E. ; Winham, S. J. ; Wolk, A. ; Woo, Y.-L. ; Wu, A. H. ; Yan, L. ; Yannoukakos, D. ; Zeinomar, N. ; Zheng, W. ; Ziogas, A. ; Berchuck, A. ; Goode, E. L. ; Huntsman, D. G. ; Pearce, C. L. ; Ramus, S. J. ; Sellers, T. A. ; Consortium, O. C. A. (Collaboration Author) ; Freedman, M. L. ; Lawrenson, K. ; Schildkraut, J. M. ; Hazelett, D. ; Plummer, J. T. ; Kar, S. ; Jones, M. R. ; Pharoah, P. D. P. ; Gayther, S. A.et al. Show all 156 authors

2024
Elsevier New York, NY

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Please use a persistent id in citations: 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.

Keyword(s): GWAS ; epithelial ovarian cancer risk ; fine mapping ; functional mechanisms

Note: 2024 Jun 6;111(6):1061-1083

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Contributing Institute(s):

1. C020 Epidemiologie von Krebs (C020)

Research Program(s):

1. 313 - Krebsrisikofaktoren und Prävention (POF4-313) (POF4-313)

Appears in the scientific report 2024

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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