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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. The majority of variants identified in these regions remain unclassified, and about 80% of germline BRCA1/2 tests result uninformative. 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. This project aimed to investigate the prevalence of germline variants in the non-coding regulatory regions of BRCA1/2 and other breast cancer predisposition genes in patients with triple-negative breast cancer (TNBC)selected for age at cancer diagnosis and/or family history of cancer. We analyzed an NGS custom panel of promoter regions of 28 genes involved in breast/ovarian cancer predisposition. We enrolled 144 TNBC patients who were previously tested negative for germline variants in the coding regions of BRCA1/2 and other cancer predisposition genes. The NGS analysis identified 635 rare variants in non- coding regions of the 28 genes, among the 144 patients. In our TNBC cohort, we observed higher prevalence of mutations in following genes CDH1 11.3%, STK11 11.2%, ATM 10.7%, PTEN 7.4%, PMS 2 5.0%. Clinical data were available for 75 patients, and were integrated with the genomic dataset. Among these 75 patients, rare germline variants in BRCA2 were statistically significantly related to worse overall survival (OS) (p-value=0.017, HR=4.76, 95% confidence interval 1.32-17.15). No differences in disease-free survival (DFS) and OS were found for the other genes. CDH1 rare variants were related to the highest percentage of non-pathological complete response after neoadjuvant chemotherapy (p=0.027); MLH1 and PALB2 rare variants were found to be both related to bilateral breast cancer (p=0.015 and p=0.0005, respectively). Rare variants of the ATM gene were associated with a positive family history (p=0.041). However, due to the small sample size, these analyses should be considered only exploratory, and further studies are needed to confirm these findings.
Palleschi et al. (Wed,) studied this question.