학술논문
A transcriptome-wide association study of high-grade serous epithelial ovarian cancer identifies new susceptibility genes and splice variants
Document Type
article
Author
Gusev, Alexander; Lawrenson, Kate; Lin, Xianzhi; Lyra, Paulo C; Kar, Siddhartha; Vavra, Kevin C; Segato, Felipe; Fonseca, Marcos AS; Lee, Janet M; Pejovic, Tanya; Liu, Gang; Karlan, Beth Y; Freedman, Matthew L; Noushmehr, Houtan; Monteiro, Alvaro N; Pharoah, Paul DP; Pasaniuc, Bogdan; Gayther, Simon A
Source
Nature Genetics. 51(5)
Subject
Language
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 × 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.