A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants.

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Lawrenson, Kate 
Lin, Xianzhi 
Lyra, Paulo C 
Kar, Siddhartha 

We sought to identify susceptibility genes for high-grade serous ovarian cancer (HGSOC) by performing a transcriptome-wide association study of gene expression and splice junction usage in HGSOC-relevant tissue types (N = 2,169) and the largest genome-wide association study available for HGSOC (N = 13,037 cases and 40,941 controls). We identified 25 transcriptome-wide association study significant genes, 7 at the junction level only, including LRRC46 at 19q21.32, (P = 1 × 10-9), CHMP4C at 8q21 (P = 2 × 10-11) and a PRC1 junction at 15q26 (P = 7 × 10-9). In vitro assays for CHMP4C showed that the associated variant induces allele-specific exon inclusion (P = 0.0024). Functional screens in HGSOC cell lines found evidence of essentiality for three of the new genes we identified: HAUS6, KANSL1 and PRC1, with the latter comparable to MYC. Our study implicates at least one target gene for 6 out of 13 distinct genome-wide association study regions, identifying 23 new candidate susceptibility genes for HGSOC.

Alternative Splicing, Carcinoma, Ovarian Epithelial, Cell Cycle Proteins, Cell Line, Tumor, Databases, Genetic, Endosomal Sorting Complexes Required for Transport, Female, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Models, Genetic, Nuclear Proteins, Ovarian Neoplasms, Polymorphism, Single Nucleotide, Transcriptome
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Nat Genet
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Springer Science and Business Media LLC
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.