Age-adjusted association of homologous recombination genes with ovarian cancer using clinical exomes as controls

BACKGROUND: Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Recent case-control studies have used allele counts alone to quantify genetic associations with cancer. METHODS: A retrospective case-control study was performed on 6,182 women with OC referred for hereditary cancer multi-gene panel testing (cases) and 4,690 mothers from trios who were referred for whole-exome sequencing (controls). We present age-adjusted odds ratios (OR(Adj)) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes. RESULTS: Significant associations with OC were observed in BRCA1, BRCA2, RAD51C and RAD51D. Other homologous recombination genes, BARD1, NBN, and PALB2, were not significantly associated with OC. ATM and CHEK2 were only significantly associated with OC by crude odds ratio (OR(Crude)) or by OR(Adj), respectively. However, there was no significant difference between OR(Crude) and OR(Adj) for these two genes. The significant association of PVs in BRIP1 by OR(Crude) (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by OR(Adj) (0.87, CI = 0.41 to 1.93, P = 0.73). Interestingly, the confidence intervals of the two effect sizes were significantly different (P = 0.04). CONCLUSION: The lack of association of PVs in BRIP1 with OC by OR(Adj) is inconsistent with some previous literature and current management recommendations, highlighted by the significantly older age of OC onset for BRIP1 PV carriers compared to non-carriers. By reporting OR(Adj), this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13053-019-0119-3) contains supplementary material, which is available to authorized users.