Abstract
BackgroundGenes 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.MethodsA 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 (ORAdj) to determine association of OC with pathogenic variants (PVs) in homologous recombination genes.ResultsSignificant 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 (ORCrude) or by ORAdj, respectively. However, there was no significant difference between ORCrude and ORAdj for these two genes. The significant association of PVs in BRIP1 by ORCrude (2.05, CI = 1.11 to 3.94, P = 0.03) was not observed by ORAdj (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).ConclusionThe lack of association of PVs in BRIP1 with OC by ORAdj 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 ORAdj, this study presents associations that reflect more informed genetic contributions to OC when compared to traditional count-based methods.
Highlights
Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association
The median age at diagnosis of pathogenic variants (PVs) carriers in OC cases ranged from 53 years in BRCA1 to 67 years in BRIP1, while the median age of testing of PV carriers in controls ranged from 32.5 years in RAD51D to 46 years in BRIP1 (Table 1)
A recent study reported no significant association of BRIP1 with OC, but our results reveal a clinically relevant factor that offers insight which may have contributed to the observed lack of association
Summary
Genes in the homologous recombination pathway have shown varying results in the literature regarding ovarian cancer (OC) association. Clinical multi-gene hereditary ovarian cancer (OC) panels include genes that function in the same homologous recombination (HR) DNA repair pathway as BRCA1 and BRCA2, such as ATM, BARD1, BRIP1, CHEK2, NBN, PALB2, RAD51C, and RAD51D These genes have been linked to hereditary ovarian cancer, but the extent to which some of these genes contribute to Identifying an appropriate control group for genetic association studies is vital for accurate estimation of cancer risks. The FLOSSIES database has been used to perform genetic association studies in women’s cancer [13] The advantage of such cohorts are the large, readily available number of genotyped individuals with diverse ancestries and varied clinical histories, but drawbacks include the lack of specific phenotypic information including age and cancer history of the participants
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