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

Abstract

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.

DNA Repair and Ovarian Carcinogenesis: Impact on Risk, Prognosis and Therapy Outcome

“…Various studies disclosed strikingly elevated risk for OvC, reflected by odds ratio for RAD51C mutations ranging from 5 to 12 [59,60]. Similar odds ratios (5 to 12) have been assessed for mutations in RAD51D [9,[61][62][63].…”

“…In the recent study, the median age at diagnosis in RAD51C and RAD51D mutation carriers was 39 and 32.5 years respectively, suggesting the involvement of RAD51 genes mutations in earlier onset of OvC [60].…”

“…Mutations associated with ↑ risk [59,60] and earlier onset [60] N/A Response to PARPi (in vivo and in vitro evidence) [64,65] RAD51D…”

“…Mutations associated with ↑ risk [9,[61][62][63] and earlier onset [60] N/A Response to PARPi (in vivo and in vitro evidence) [65] RAD50 Mutated in about 0.12% of tumors [66] Copy number deletion associated with ↑ OS and PFS [69] In vitro knock-down associated with better response to PARPi [69] PALB2…”

Literature Review of BARD1 as a Cancer Predisposing Gene with a Focus on Breast and Ovarian Cancers

“…These findings are interesting because these variants may result in partial or complete loss of BARD1 protein. In studies of ≥500 cancer cases, the prevalence of potentially pathogenic BARD1 variants ranged from 0.18-0.53% [11,47], 0.67-0.9% [13,22], and 0.07-0.23% [37,63] in BC, TNBC and OC cases, respectively. Clearly, in BC and OC cases carriers of BARD1 variants are much less common than carriers of pathogenic BRCA1/BRCA2 variants (5-10% each).…”