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.
Subject(s)
Carcinoma, Ovarian Epithelial/genetics , Ovarian Neoplasms/genetics , Alternative Splicing , Cell Cycle Proteins/genetics , Cell Line, Tumor , Databases, Genetic , Endosomal Sorting Complexes Required for Transport/genetics , Female , Gene Expression Regulation, Neoplastic , Gene Knockout Techniques , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Models, Genetic , Nuclear Proteins/genetics , Polymorphism, Single Nucleotide , TranscriptomeABSTRACT
OBJECTIVE: Genome-wide association studies (GWASs) for epithelial ovarian cancer (EOC) have focused largely on populations of European ancestry. We aimed to identify common germline variants associated with EOC risk in Asian women. METHODS: Genotyping was performed as part of the OncoArray project. Samples with >60% Asian ancestry were included in the analysis. Genotyping was performed on 533,631 SNPs in 3238 Asian subjects diagnosed with invasive or borderline EOC and 4083 unaffected controls. After imputation, genotypes were available for 11,595,112 SNPs to identify associations. RESULTS: At chromosome 6p25.2, SNP rs7748275 was associated with risk of serous EOC (odds ratio [OR]â¯=â¯1.34, Pâ¯=â¯8.7â¯×â¯10-9) and high-grade serous EOC (HGSOC) (ORâ¯=â¯1.34, Pâ¯=â¯4.3â¯×â¯10-9). SNP rs6902488 at 6p25.2 (r2â¯=â¯0.97 with rs7748275) lies in an active enhancer and is predicted to impact binding of STAT3, P300 and ELF1. We identified additional risk loci with low Bayesian false discovery probability (BFDP) scores, indicating they are likely to be true risk associations (BFDP <10%). At chromosome 20q11.22, rs74272064 was associated with HGSOC risk (ORâ¯=â¯1.27, Pâ¯=â¯9.0â¯×â¯10-8). Overall EOC risk was associated with rs10260419 at chromosome 7p21.3 (ORâ¯=â¯1.33, Pâ¯=â¯1.2â¯×â¯10-7) and rs74917072 at chromosome 2q37.3 (ORâ¯=â¯1.25, Pâ¯=â¯4.7â¯×â¯10-7). At 2q37.3, expression quantitative trait locus analysis in 404 HGSOC tissues identified ESPNL as a putative candidate susceptibility gene (Pâ¯=â¯1.2â¯×â¯10-7). CONCLUSION: While some risk loci were shared between East Asian and European populations, others were population-specific, indicating that the landscape of EOC risk in Asian women has both shared and unique features compared to women of European ancestry.
