BRCA1/2 reversion mutations in a pan-cancer cohort

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Homologous recombination deficiency (HRD) mutations increase tumor sensitivity to platinum (Pt)-based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors.
• Reversion mutations can restore protein function, leading to acquired resistance to these therapies.
• Comprehensive characterization of BRCA1/2 reversion mutations in pan-cancer cohorts is lacking.

Purpose of the Study:

• To characterize BRCA1/2 reversion mutations in a large pan-cancer cohort of Japanese patients.
• To investigate the frequency and types of BRCA1/2 reversion mutations.
• To explore the clinical context of these mutations in relation to treatment response.

Main Methods:

• Retrospective analysis of sequencing data from 3738 Japanese patients with 32 cancer types.
• Identification of somatic mutations in tumor or circulating cell-free DNA restoring the open reading frame (ORF) of BRCA1/2.
• Analysis of reversion event types (deletions, single-nucleotide variants, multinucleotide variants, deletion-insertions) and their mechanisms (e.g., microhomology-mediated end-join repair).

Main Results:

• Identified 12 patients (0.32%) with somatic BRCA1 (n=3) and BRCA2 (n=9) reversion mutations.
• Reversion mutations were found in breast, ovarian/fallopian tube/peritoneal, pancreatic, prostate, and gallbladder cancers.
• Identified 21 reversion events, with 7 deletions (33.3%) showing microhomology >1 bp, suggesting microhomology-mediated end-join repair.
• Four patients acquired mutations after PARP-inhibitor failure, two after platinum-based treatment progression, and five after both treatments.

Conclusions:

• Somatic BRCA1/2 reversion mutations occur in a small fraction of Japanese cancer patients, leading to acquired resistance.
• These mutations can arise after treatment with platinum-based chemotherapy and/or PARP inhibitors.
• The findings suggest that reversion mutations may be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies, warranting further investigation.