Abstract 1359: Somatic involution of pathogenic BRCA1 germline mutations

There is currently a wealth of data on the tumor genomic contexture from BRCA1/2 carriers, particularly breast and ovarian carcinomas. By contrast, little attention has as yet been paid to the genomic status of cancer-related normal tissues from these individuals. Here, we investigated the status of pathogenic BRCA1 germline mutations (GM) in breast (B) and gynecologic (GYN) tissues. Methods: We examined 121 DNA samples (48 B; 36 GYN; 37 tumors) from an equal number of paraffin blocks obtained upon prophylactic or debulking surgery from 44 BRCA1/2 carriers (mean age 38 yrs, range 24-62; 43 BRCA1 carriers). Six women had never had cancer manifestation (CM). At the time of surgery, 32 were cancer-free but had received neo- or adjuvant chemotherapy, and 6 had concurrent cancer without prior treatment. Following multimethod DNA quality control, mutation validation and sample identity match to exclude false negatives, we interrogated GM presence in tissues in comparison to clinicopathologic data and tumor genotypes (60-gene panel; mean read depth over 800). Results: In 19 samples from 13 BRCA1 carriers, including 13 normal B/GYN and 6 tumors, the germline mutation was present at frequencies lower than 5% (observed with the integrated genome viewer) up to 12%, or it was undetectable with Sanger sequencing and multiplex PCR. This condition, termed GM-loss, was present in 13 GYN, 12 of which in the histologically normal tube, and in only 3 B with fibrocystic disease (p=0.0210). It was also present in one ovarian thecoma but it was absent in usual or atypical hyperplasia in B. GM-loss was observed in 9/55 normal tissues from breast cancer and in 4/6 normal tissues from ovarian cancer patients, while it was absent in the normal tissues from women without CM (p=0.0002). GM-loss mostly affected the BRCA1 BRCT functional domain (p