Combined Tumor Sequencing and Case-Control Analyses of RAD51C in Breast Cancer

Abstract

Background Loss-of-function variants in RAD51C are associated with familial ovarian cancer, but its role in hereditary breast cancer remains unclear. The aim of this study was to couple breast tumor sequencing with case-control data to clarify the contribution of RAD51C to hereditary breast cancer. Methods RAD51C was sequenced in 3080 breast cancer index cases that were negative in BRCA1/2 clinical tests and 4840 population-matched cancer-free controls. Pedigree and pathology data were analyzed. Nine breast cancers and one ovarian cancer from RAD51C variant carriers were sequenced to identify biallelic inactivation of RAD51C, copy number variation, mutational signatures, and the spectrum of somatic mutations in breast cancer driver genes. The promoter of RAD51C was analyzed for DNA methylation. Results A statistically significant excess of loss-of-function variants was identified in 3080 cases (0.4%) compared with 2 among 4840 controls (0.04%; odds ratio = 8.67, 95% confidence interval = 1.89 to 80.52, P< .001), with more than half of the carriers having no personal or family history of ovarian cancer. In addition, the association was highly statistically significant among cases with estrogen-negative (P <. 001) or triple-negative cancer (P < .001), but not in estrogen-positive cases. Tumor sequencing from carriers confirmed bi-allelic inactivation in all the triple-negative cases and was associated with high homologous recombination deficiency scores and mutational signature 3 indicating homologous recombination repair deficiency. Conclusions This study provides evidence that germline loss-of-function variants of RAD51C are associated with hereditary breast cancer, particularly triple-negative type. RAD51C-null breast cancers possess similar genomic and clinical features to BRCA1-null cancers and may also be vulnerable to DNA double-strand break inducing chemotherapies and poly ADP-ribose polymerase inhibitors.

Detection of Germline Mutations in Breast Cancer Patients with Clinical Features of Hereditary Cancer Syndrome Using a Multi-Gene Panel Test

“…They found that 16.9% of included patients carried BRCA1/2 mutations and 6.8% of patients had non-BRCA1/2 mutations including TP53, PALB2, CHEK2, ATM, BARD1, BRIP, CDH1 and RAD50. Recent studies reported that mutations in PALB2 and RAD51C were found to be an important cause of HBOC [24,25]. Additionally, CDH1 mutations were not found in the Western study but detected in the Chinese study.…”

BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases

“…In contrast to mutations in BRCA1 and BRCA2, which predispose individuals to both BC and OC, BRIP1, RAD51C, and RAD51D are predominantly OC risk genes, while their role in BC is less defined and questionable [20,21,27,74,75,[93][94][95][96]. Despite certain relationships between mutations in the discussed genes and OC, more precise risk estimation is required.…”

Analysis of BRCA1 and RAD51C Promoter Methylation in Italian Families at High-Risk of Breast and Ovarian Cancer

“…While BRCA1 is the most recognized predisposing gene for BC and OC, RAD51C was first identified as a putative cancer-predisposing gene in BC/OC families in 2010 [15]. Subsequently, it was confirmed to be associated with an increased risk of OC and, only recently, of BC, in particular of the TN type [16,17]. Moreover, to date somatic epimutations in both BC [5,10,18,19] and OC [10,19,20] have been identified only at these two genes.…”