Kei Takeshita

Tumor sensitivity to platinum (Pt)‐based chemotherapy and poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors is increased by homologous recombination deficiency‐causing mutations; in particular, reversion mutations cause drug resistance by restoring protein function. Treatment response is predicted by breast cancer susceptibility gene 1/2 ( BRCA1/2 ) mutations; however, BRCA1/2 reversion mutations have not been comprehensively studied in pan‐cancer cohorts. We aimed to characterize BRCA1/2 reversion mutations in a large pan‐cancer cohort of Japanese patients by retrospectively analyzing sequencing data for BRCA1/2 pathogenic/likely pathogenic mutations in 3738 patients with 32 cancer types. We identified somatic mutations in tumors or circulating cell‐free DNA that could restore the ORF of adverse alleles, including reversion mutations. We identified 12 (0.32%) patients with somatic BRCA1 ( n = 3) and BRCA2 ( n = 9) reversion mutations in breast ( n = 4), ovarian/fallopian tube/peritoneal ( n = 4), pancreatic ( n = 2), prostate ( n = 1), and gallbladder ( n = 1) cancers. We identified 21 reversion events— BRCA1 ( n = 3), BRCA2 ( n = 18)—including eight pure deletions, one single‐nucleotide variant, six multinucleotide variants, and six deletion–insertions. Seven (33.3%) reversion deletions showed a microhomology length greater than 1 bp, suggesting microhomology‐mediated end‐join repair. Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP‐inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt‐based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA ‐associated cancers, our findings suggest that reversion mutations due to Pt‐chemotherapy might be correlated with BRCA1/2 ‐mediated tumorigenesis even in non‐ BRCA ‐associated histologies.