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

Document Type

Article

Publication Date

5-1-2019

Publication Title

Nature genetics

Abstract

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

PubMed ID

31043753

Volume

51

Issue

5

First Page

815

Last Page

823

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