A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants
Gusev A, Lawrenson K, Lin X, Lyra PC, Jr., Kar S, Vavra KC, Segato F, Fonseca MAS, Lee JM, Pejovic T, Liu G, Karlan BY, Freedman ML, Noushmehr H, Monteiro AN, Pharoah PDP, Pasaniuc B, and Gayther SA. A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants. Nat Genet 2019; 51(5):815-823.
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 x 10(-9)), CHMP4C at 8q21 (P = 2 x 10(-11)) and a PRC1 junction at 15q26 (P = 7 x 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.
Medical Subject Headings
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