Common variants at 19p13 are associated with susceptibility to ovarian cancer

Abstract

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecological malignancy in the developed world, accounting for 4% of the deaths from cancer in women. We performed a three-phase genome-wide association study of EOC survival in 8,951 individuals with EOC (cases) with available survival time data and a parallel association analysis of EOC susceptibility. Two SNPs at 19p13.11, rs8170 and rs2363956, showed evidence of association with survival (overall P = 5 × 10⁻⁴ and P = 6 × 10⁻⁴, respectively), but they did not replicate in phase 3. However, the same two SNPs demonstrated genome-wide significance for risk of serous EOC (P = 3 × 10⁻⁹ and P = 4 × 10⁻¹¹, respectively). Expression analysis of candidate genes at this locus in ovarian tumors supported a role for the BRCA1-interacting gene C19orf62, also known as MERIT40, which contains rs8170, in EOC development.

Figure 1. Genomic and transcript analysis of the MERIT40 and ANKLE1 genes in the 19p13 ovarian cancer susceptibility region

(a) Genomic architecture of the 19p13.11 region containing the two SNPs most significantly associated with EOC risk (rs8170 and rs2363956). SNPs are located with respect to genes within this region. rs8170 is located in MERIT40 and rs2363956 is located in ANKLE1. (b) Whole genome array comparative genomic hybridization (aCGH) analysis of 105 serous, invasive ovarian cancers displays the range of copy number changes throughout the genome, along the length of each chromosome. Green = frequency of copy number gain; red = copy number loss. (c) Higher resolution aCGH map of chromosome 19 indicates that this chromosome is frequently amplified in EOCs with an amplification peak at the 19p13.11 susceptibility locus (blue line); 48/105 tumors (46%) showed copy number gain at 19p13.11 compared to 2/105 tumors (2%) that showed copy number loss. (d & e) Transcript expression of MERIT40 and ANKLE1 in 48 normal primary ovarian epithelial (POE) cell lines compared and 23 OC cell lines detected using real time RT-PCR. For each gene, transcript expression is normalized against β-actin; genes expression normalized against a second endogenous control, GAPDH, showed similar trends (Supplementary figure 4). MERIT40 expression is significantly higher in OC cell lines compared to POE cells (d), but there was no difference in ANKLE1 expression between OC and POE cells (e). (f) Expression data from the Cancer Genome Atlas Project (http://cancergenome.nih.gov) for MERIT40 and ANKLE1 genes analyzed in 216 serous EOCs. The graph shows proportion of tumors that show loss or gain of expression with >0.5 fold change relative to pooled ‘normal’ samples.