Exploring the role of rare germline variants in non-coding regions of cancer predisposition genes in triple-negative breast cancer patients

BRCA1 and BRCA2 are well-known genes that are associated with a significant increase in the risk of breast and ovarian cancers. However, current genetic screening 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. As a result, the majority of variants identified in these regions remain unclassified, and about 80% of germline BRCA1/2 tests result in a "negative" diagnosis. Introns and proximal untranslated regions remain relatively unexplored, but evidence of non-coding variants' impact on cancer risk and response to treatment is beginning to emerge. The aim of this project was to investigate the prevalence of non-BRCA pathogenic germline variants in patients with triple-negative breast cancer and risk factors, the authors used an NGS custom panel of promoter regions of 62 genes involved in cancer predisposition. We enrolled 144 consecutive triple-negative breast cancer patients who were wild type for germline BRCA1/2 and identified 635 rare variants in non-coding regions of 28 genes, among the 144 patients. Clinical data were available for 75 patients, and these data were merged with the genomic dataset. Among these 75 patients, rare germline variants in BRCA2 were statistically significantly related to worse overall survival (p-value=0.017 HR=4.76 (1.32-17.15)). No differences in Disease-free survival and overall survival were found for other genes. CDH1's rare variants were related to the highest percentage of non-pathological complete response after neoadjuvant chemotherapy (p-value=0.0273); MLH1 and PALB2 rare variants were found to be both related to bilateral breast cancer (p-value=0.0146 and p=0.0005, respectively). Rare variants of the ATM gene were associated with a positive family history (p-value 0.0408). However, due to the small sample size, these analyses should be considered only exploratory, and further studies are needed to confirm these findings.