Genomic Instability in Non-Breast or Ovarian Malignancies of Individuals with Germline Pathogenic Variants in BRCA1/2

Background: Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non-breast or ovarian malignancies that have BRCA1/2 deficiency and genomic instability features. Methods: The full tumor history of a large, historical, clinic-based, consecutive cohort of 2965 individuals with germline pathogenic variants in BRCA1/2 was retrieved from the Dutch nationwide pathology databank (Palga). In total, 169 non-breast or ovarian malignancies were collected and analyzed using targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second-hit alterations and genomic instabilities indicative of homologous recombination deficiency, respectively. Results: BRCA1/2 deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively). Conclusions: BRCA1/2 deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. Evaluation of the effectiveness of poly(ADP-ribose) polymerase inhibitors in these individuals should be focused on tumors with a confirmed absence of a wild-type allele.