Most female carriers of germline BRCA1 mutation develop breast/ovarian cancer during the lifetime. However, the penetrance of BRCA1 pathogenic variants does not reach 100%, and the age of BRCA1-associated breast cancer (BC) onset varies widely. BRCA1-driven tumors are chromosomally unstable and may have excessive antigenicity. We hypothesized that hereditary variations in immune response pathways may contribute to the variability of BRCA1 penetrance. We evaluated whether genetic variations in the immune response-related genes contribute to this heterogeneity.
The entire coding sequence of 353 immune response genes was analyzed by NGS in 54 young (<39 y.o.) and 59 senior (>57 y.o.) BRCA1-mutated BC patients. Newly identified candidate variants were genotyped in the extended study, which included 185 young and 167 senior BC Slavic patients affected by BRCA1-driven BC.
NGS analysis identified 54 allelic variants with gnomAD frequency <5% and a CADD-score of at least>/= 25, which were found exclusively either in young or in senior patients. The prevalence of 26 top candidates was analyzed in the extension study. The known pathogenic variant in the perforin gene (PRF1 p.Ala91Val) was significantly overrepresented in young BC patients compared with senior women (20 /carriers from 239 (8.4%) vs. 8/226 (3.5%), p = 0.032). PRF1 p.Ala91Val heterozygosity was associated with significant elevation of the risk of acquiring BC before the age of 39 years as compared to the BRCA1 mutation carriers with the wild-type PRF genotype [OR = 2.49, 95% CI: 1.073 - 5.771, p = 0.034].
Perforin is one of the principal cytotoxic proteins responsible for cell lysis mediated by T-lymphocytes and NK cells. PRF1 p.Ala91Val heterozygosity is known to be associated with subclinical symptoms of immunodeficiency. This study suggests that the PRF1 p.Ala91Val substitution may compromise antitumor immune response and support the development of tumors in BRCA1 carriers. This study revealed that the inherited haploinsufficiency of immunodeficiency-related gene PRF1 caused by pathogenic missense p.Ala91Val may increase the risk of early breast cancer manifestation in BRCA1 mutation carriers.
Clinical trial identification
Legal entity responsible for the study
RSF grant #19-15-00207
All authors have declared no conflicts of interest.