BRCA1/2 reversion mutations in a pan-cancer cohort
Kohei Nakamura1,2, Hideyuki Hayashi1, Ryutaro Kawano1
1Genomics Unit, Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
Abstract:
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.
Insights
Somatic BRCA1/2 reversion mutations can restore protein function, leading to drug resistance in cancer patients. This study identified these resistance mutations in 12 Japanese patients across 32 cancer types, highlighting their occurrence even in non-BRCA-associated cancers.
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.
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