Variant of uncertain context.
The Study: As we see more and more next-generation sequencing reports, we see more and more somatic tumor mutations in BRCA1 or BRCA2. In this study, matched blood and tumor samples from over 17K patients with advanced cancer were sequenced for both somatic loss-of-function (LoF) mutations and pathogenic germline mutations in BRCA1 and BRCA2. Importantly, the authors divided the cohort into known BRCA-associated (as in breast, ovary, prostate, and pancreas) and unknown BRCA-associated cancer types. Overall, 3% of patients had germline BRCA-mutations while 2% had somatic LoF mutations. Most importantly, among unknown BRCA-associated cancer types, none of the classic hallmarks were seen; instead, they were more likely to harbor somatic mutations that had little impact on homologous recombination repair or PARP-inhibitor sensitivity. In other words, BRCA-mutations in unknown BRCA-associated cancers don’t seem to have the same clinical phenotype we expect to see in known BRCA-associated cancers, likely because they result from tumorigenesis rather than cause it. Conversely, the BRCA-phenotype was commonly seen among known BRCA-associated cancer types regardless of whether they had heterozygous or biallelic BRCA-loss or had germline or somatic mutations. Interestingly, prostate cancer appeared to fall into both types.
TBL: Neither germline nor somatic BRCA-mutations carry similar significance in known versus unknown BRCA-associated cancer types. | Jonsson, Nature 2019