BRCA1 and BRCA2 mutations are widely recognized for their role in homologous recombination deficiency (HRD) and their clinical relevance in predicting response to PARP inhibitors. However, emerging genomic evidence reveals a complex picture, especially when these mutations occur in tumors with microsatellite instability-high (MSI-H) status. Recent studies suggest that BRCA1/2 mutations in MSI-H tumors are often “passenger” events, raising critical questions about treatment decisions and the role of comprehensive genomic profiling.
Key Findings: Monoallelic and Non-HRD BRCA Mutations in MSI-H Tumors
Though HRD and MSI-H typically represent mutually exclusive pathways, BRCA1/2 mutations do appear in MSI-H tumors. However, they tend to:
As reported by Rajagopal et al, these variants frequently occur in microsatellite tracts, leading to frameshift mutations in BRCA1 and BRCA2, such as:
This pattern suggests they are likely passenger mutations, not functionally driving genomic instability.
Why Are BRCA Mutations Common in MSI-H Tumors?
MSI-H cancers—characterized by defects in mismatch repair (MMR) genes—accumulate a high burden of insertion/deletion mutations. This hypermutability results in:
These numbers highlight a critical insight: the presence of BRCA mutations in MSI-H tumors doesn’t always indicate a functional deficiency in homologous recombination.
Clinical Impact: Rethinking PARP Inhibitor Use in MSI-H + BRCA-Mutated Cancers
Standard guidelines support the use of PARP inhibitors in cancers harboring pathogenic BRCA1/2 mutations. However, when these mutations co-occur with MSI-H, the therapeutic response to PARP inhibition appears limited.
Two illustrative prostate cancer cases from a recent study by Kwan et al, demonstrate this:
The co-occurrence of BRCA1/2 mutations and MSI-H status presents a diagnostic and therapeutic challenge as shown below.
To optimize clinical outcomes, comprehensive genomic profiling (CGP) in standard-of-care settings can provide a holistic view that includes MSI status, TMB, BRCA zygosity, gLOH, and the broader mutational landscape. This integrated approach ensures treatment decisions are guided by the functional relevance of mutations, enabling clinicians to align therapies with the tumor’s true biological behavior.