BRCA1/2 reversion mutations in a pan-cancer cohort

Cancer Sci. 2024 Feb;115(2):635-647. doi: 10.1111/cas.16033. Epub 2023 Dec 1.


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.

Keywords: BRCA1/2; PARP inhibitor; homologous recombination deficiency; platinum-based chemotherapy; reversion mutation.

MeSH terms

  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Female
  • Germ-Line Mutation
  • Humans
  • Male
  • Mutation
  • Ovarian Neoplasms* / genetics
  • Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use
  • Poly(ADP-ribose) Polymerases
  • Retrospective Studies


  • Poly(ADP-ribose) Polymerase Inhibitors
  • BRCA1 protein, human
  • BRCA1 Protein
  • BRCA2 protein, human
  • BRCA2 Protein
  • Poly(ADP-ribose) Polymerases