Summary of BARD1 Mutations and Precise Estimation of Breast and Ovarian Cancer Risks Associated with the Mutations

Abstract

Over the last two decades, numerous BARD1 mutations/pathogenic variants (PVs) have been found in patients with breast cancer (BC) and ovarian cancer (OC). However, their role in BC and OC susceptibility remains controversial, and strong evidence-based guidelines for carriers are not yet available. Herein, we present a comprehensive catalog of BARD1 PVs identified in large cumulative cohorts of ~48,700 BC and ~20,800 OC cases (retrieved from 123 studies examining the whole coding sequence of BARD1). Using these resources, we compared the frequency of BARD1 PVs in the cases and ~134,100 controls from the gnomAD database and estimated the effect of the BARD1 PVs on BC and OC risks. The analysis revealed that BARD1 is a BC moderate-risk gene (odds ratio (OR) = 2.90, 95% CIs:2.25–3.75, p < 0.0001) but not an OC risk gene (OR = 1.36, 95% CIs:0.87–2.11, p = 0.1733). In addition, the BARD1 mutational spectrum outlined in this study allowed us to determine recurrent PVs and evaluate the variant-specific risk for the most frequent PVs. In conclusion, these precise estimates improve the understanding of the role of BARD1 PVs in BC and OC predisposition and support the need for BARD1 diagnostic testing in BC patients.

BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

“…Contrarily, the analysis of 3261 epithelial OC cases by Ramus et al and 6294 OC cases by Lilyquist et al resulted in non-significant associations of deleterious BARD1 variants with OC risk [17,19]. The meta-analysis by Suszynska and Kozlowski could not detect an association of BARD1 with OC risk in a cumulative set of~20,800 OC cases either [30].…”

“…Similarly, Slavin et al reported an OR = 3.18 (CI = 1.34-7.36; p = 0.012) [10] and Weber-Lassalle et al reported an OR = 5.35 (CI = 3.17-9.04; p < 0.00001) [11] in 2134 and 4469 familial BC patients, respectively. Besides, a recent meta-analysis by Suszynska and Kozlowski collected data from a total of 123 published studies and consistently reported an OR = 2.90 (CI = 2.25-3.75; p < 0.0001) over a cumulative cohort of~48,700 BC patients [30]. However, there are some studies that failed to identify a significant association with BC risk, such as those published by Castéra et al and Lu et al [15,16].…”

Do BARD1 Mutations Confer an Elevated Risk of Prostate Cancer?

“…The BARD1 and BRCA1 proteins form a heterodimer complex. The interaction between the two proteins is essential for maintaining the stabilization of BRCA1 [ 14 , 19 , 20 , 21 ]. The BRCA1/BARD1 heterodimer acts in the DNA damage response signaling pathway, cell cycle control, hormone signaling modulation and chromatin structural maintenance [ 22 , 23 ].…”

“…To date, little is known about cancer susceptibility in carriers of BARD1 mutations. The most commonly studied is the association between BARD1 and breast cancer [ 19 , 20 , 27 ]. Most recent, large association analysis of approximately 110,000 women performed by Breast Cancer Association Consortium provided evidence of an association between truncating BARD1 mutation and an elevated risk of breast cancer [ 13 ].…”

“…This complex has activity of E3 ubiquitin ligase, is involved in DNA damage repair, cell cycle control, regulation of hormone signaling, and apoptosis [ 15 ]. Because BRCA1 is a prostate cancer susceptibility gene (with an estimated risk for prostate cancer of two- to four-fold by the age of 65) [ 16 , 17 , 18 , 19 ], and the BRCA1 protein interacts with the BARD1 protein, we considered BARD1 to be a candidate prostate cancer susceptibility gene. We sequenced the BARD1 gene in 390 Polish men with hereditary prostate cancer.…”