A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.
Lyra, Paulo C
Vavra, Kevin C
Fonseca, Marcos AS
Lee, Janet M
Ovarian Cancer Association Consortium,
Karlan, Beth Y
Freedman, Matthew L
Nature Publishing Group
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Gusev, A., Lawrenson, K., Lin, X., Lyra, P. C., Kar, S., Vavra, K. C., Segato, F., et al. (2019). A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.. Nature genetics, 51 (5), 815-823. https://doi.org/10.1038/s41588-019-0395-x
Although genome-wide association studies (GWASs) have identified >30 different regions harboring risk variants for high grade serous ovarian cancer (HGSOC), the genes contributing to risk remain largely unknown. Here, we sought to identify HGSOC susceptibility genes by integrating genetic predictors of alternative splicing and total expression in different HGSOC-relevant tissue types (N=2,169) with the largest GWAS available for HGSOC (N=13,037 cases/40,941 controls). We performed a multi-tissue transcriptome-wide association study (TWAS) across >70,000 significantly heritable gene/exon features to identify 25 TWAS significant genes, 7 of which were significant at the exon level only. Notable signals include LRRC46 at 19q21.32, (TWAS P=1x10-9) as well as CHMP4C at 8q21 (TWAS P=2x10-11) and PRC1 at 15q26 (TWAS P=7x10-9, significant only in an exon-level TWAS). In vitro assays for CHMP4C showed the splice event in CHMP4C induces allele specific exon inclusion (P = 0.0024); functional screens in HGSOC cell lines found evidence of essentiality for three of the novel genes we identified: HAUS6, KANSL1 and PRC1. PRC1 showed levels of essentiality comparable to that of CMYC and genes associated through splicing had significantly higher mean essentiality scores than those associated through overall expression. In sum, gene expression and splicing events implicated at least one target gene for 6/13 distinct genome-wide significant regions and revealed 2 previously reported and 23 novel candidate susceptibility genes for HGSOC.
Ovarian Cancer Association Consortium, Cell Line, Tumor, Humans, Ovarian Neoplasms, Genetic Predisposition to Disease, Cell Cycle Proteins, Nuclear Proteins, Gene Expression Regulation, Neoplastic, Alternative Splicing, Polymorphism, Single Nucleotide, Models, Genetic, Databases, Genetic, Female, Genome-Wide Association Study, Gene Knockout Techniques, Endosomal Sorting Complexes Required for Transport, Transcriptome, Carcinoma, Ovarian Epithelial
This work was supported by multiple grants: An NIH/NCI R21 award “The Role of Splice Quantitative Traits in Ovarian Cancer Pathogenesis” (CA22007801); an NIH/NCI U19 award “Follow-up of Ovarian Cancer genetic association and Interaction studies (FOCI)” as part of the Genetic Mechanisms in Oncology (GAME-ON) consortium (CA148112); an NIH/NCI R01 award “Functional Effects of Ovarian Cancer Risk Variants” (CA211707); an NIH/NCI R01 award “Functional Effects of Ovarian Cancer Risk Variants” (CA211707); an NIH/NCI R01 award “Epidemiology and biology of lncRNAs in ovarian cancer” (CA207456); and an NIH/NCI R01 award “Identifying causal variants and genes underlying breast cancer risk loci” (CA204954). The results shown here are in part based upon data generated by the TCGA Research Network: http://cancergenome.nih.gov/. Some of the normal tissue specimens were collected as part of the USC Jean Richardson Gynecologic Tissue and Fluid Repository, which is supported by a grant from the USC Department of Obstetrics & Gynecology and the NCT Cancer Center Shared Grant award P30 CA014089 (to the Norris Comprehensive Cancer Center). S.A.G is additionally supported by the Barth Family Chair in Cancer Genetics at Cedar-Sinai Medical Center. K.L. is supported in part by a K99/R00 Pathway to Independence Award from the NIH (R00CA184415) and institutional support from the Samuel Oschin Comprehensive Cancer Institute at Cedars-Sinai Medical Center. H.N. and M.A.S.F. are supported by grants 2015/07925-5 and 2017/08211-1 from Sao Paulo Research Foundation (FAPESP). H.N. is also supported by an institutional grant (Henry Ford Hospital). This work was supported in part by the Ovarian Cancer Research Fund Alliance Program Project Development Grant (373356): Co-Evolution of Epithelial Ovarian Cancer and Tumor Stroma. Additional support for this work came from NIH/NCI grants 1R01CA211707 and 1R01CA207456 and OCRF award 258807.
External DOI: https://doi.org/10.1038/s41588-019-0395-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/289402