Abstract
e13055 Background: Genomic alterations in normal tissues from pathogenic germline BRCA1/2 mutation (mut) carriers are as yet poorly described. We investigated the genomic status of normal breast (NB) and hystero-salpingo-oophorectomy (GYN) tissues removed upon prophylactic surgery in a real-life cohort of BRCA1/2 carriers. Methods: By using targeted NGS we examined the mut status of 220 samples (39 peripheral blood and 181 paraffin tissue) from 53 BRCA1/2 carriers who underwent prophylactic surgery, 42 with and 11 without prior cancer manifestation (PCM). We compared germline BRCA1/2 mut status with tumor, NB and GYN mut status. Results: Eight patients carried germline BRCA2 and 45 BRCA1 mut. Somatic mut were most frequent in BRCA2 (28%), BRCA1 (17%), TP53 (7%) among 136 NB and GYN samples; and, in TP53 (49%; p < 0.001) and BRCA1 (38%; p = 0.039) among 45 tumor samples. Among all tissue types, the 85 NB had the lowest mut load (p = 0.001). In NB and GYN, mut load was higher in BRCA1 vs. BRCA2 carriers (p = 0.027) and in those with BRCA1 substitutions/indels vs. exon deleting and skipping mut (p < 0.001). In tumors, only germline BRCA1 substitutions/indels were associated with higher mut load (p = 0.014). Preservation of germline mut in tissues was assessable in 84 samples from 26 patients. The germline mut was lost in 8 tumor and NB samples from 6 patients (23%) with PCM. Somatic deleterious mut in the BRCA1 BRCT-domain emerged in two such cases; the rest had combinations of TP53, MRE11A and NF1 mut. GYN samples from these patients retained the germline mut and presented the highest mut load among all examined samples (p < 0.001). Conclusions: Somatic mut in normal tissues from BRCA1/2 carriers are affected by the inherited mutated gene and by the type of the germline mut concerning BRCA1. Germline BRCA1 mut may be substituted by somatic mut in tumor and normal tissues, in an organ specific manner. Mutagenesis in tumors and normal tissues appear to be driven by different pathways. Our findings shed new light on the biological impact of BRCA1/2 mut in tissues.
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