Exploring the promoter regions of cancer predisposition genes in patients with triple-negative breast cancer reveals the presence of rare germline variants

Background Current genetic screening for predisposition to breast cancer (BC) is limited to BRCA1/2 exons and intron/exon boundaries, and limited information exists about the impact of variants in BRCA1/2 non-coding regions. The majority of alterations identified in these regions remain unclassified, but evidence of the impact of variants in the regulatory regions on cancer risk and response to treatment is emerging.Patients and methods This project aimed to investigate the prevalence of germline variants in the non-coding regulatory regions of BRCA1/2 and other BC predisposition genes in patients with triple-negative BC (TNBC) selected for age at cancer diagnosis and/or family history of cancer. The study also aims to investigate the relationship between these variants and clinical outcomes such as overall survival, disease-free survival (DFS), and response to treatment. We analyzed a Next-Generation Sequencing (NGS) custom panel of promoter regions of 28 genes involved in BC predisposition on 144 patients with TNBC previously tested wild type for coding regions of BRCA1/2.Results The NGS analysis identified 635 rare variants in promoter regions of the 28 genes. Among the 144 patients, for 75 with available clinical data, rare germline variants in BRCA2 promoter were statistically significantly related to worse overall survival (OS) (P-value = .017). No differences in DFS and OS were found for the other genes. Rare variants in the CDH1 promoter were related to the highest percentage of non-pathological complete response after neoadjuvant chemotherapy (P = .0273); MLH1 and PALB2 rare non-coding variants were found to be both related to bilateral BC (P = .0146 and P = .0005, respectively) and ATM promoter variants were associated with a positive family history (P = .041).Conclusion Our results underscore the importance of searching for rare germline variants in regulatory regions of cancer predisposition genes in patients with TNBC, since these variants can be associated with an increased cancer risk.