Resistance to therapy caused by intragenic deletion in BRCA2
Abstract
Cells with loss of BRCA2 function are defective in homologous recombination (HR) and are highly sensitive to inhibitors of poly(ADP-ribose) polymerase (PARP), which provides the basis for a new therapeutic approach. Here we show that resistance to PARP inhibition can be acquired by deletion of a mutation in BRCA2. We derived PARP-inhibitor-resistant (PIR) clones from the human CAPAN1 pancreatic cancer cell line, which carries the protein-truncating c.6174delT frameshift mutation. PIR clones could form DNA-damage-induced RAD51 nuclear foci and were able to limit genotoxin-induced genomic instability, both hallmarks of a competent HR pathway. New BRCA2 isoforms were expressed in the resistant lines as a result of intragenic deletion of the c.6174delT mutation and restoration of the open reading frame (ORF). Reconstitution of BRCA2-deficient cells with these revertant BRCA2 alleles rescued PARP inhibitor sensitivity and HR deficiency. Most of the deletions in BRCA2 were associated with small tracts of homology, and possibly arose from error-prone repair caused by BRCA2 deficiency. Similar ORF-restoring mutations were present in carboplatin-resistant ovarian tumours from c.6174delT mutation carriers. These observations have implications for understanding drug resistance in BRCA mutation carriers as well as in defining functionally important domains within BRCA2.
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Mutational scars represent genomic history and not current on-going mutational processes that can result in false positive CHORD predictions.
“We do acknowledge that mutational scars represent genomic history and not current on-going mutational processes that can result in false positive CHORD predictions, which could be for example due to reversion of HRD by secondary frameshifts34,35, or recent acquisition of the HRD phenotype.”
From Pan-cancer landscape of homologous recombination deficiency. (2020) · cites this paper as [35]
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- Authors
- Edwards, S. L., Brough, R., Lord, C. J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S., & Ashworth, A.
- Affiliations
- Institute of Cancer Research (GB)
- Memorial Sloan Kettering Cancer Center (US)
- Memorial Health University Medical Center (US)
- Corresponding author
- Ashworth, Alan
- ORCID
- Venue
- Nature
- Published
- 2008-02
- Volume
- 451
- Issue
- 7182
- Pages
- 1111-1115
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2065849886
- Cited by
- 1,011
- References
- 2
- Citations by year
- 2026: 30 · 2025: 38 · 2024: 45 · 2023: 43 · 2022: 56 · 2021: 80 · 2020: 65 · 2019: 46 · 2018: 50 · 2017: 64 · 2016: 54 · 2015: 39 · 2014: 45 · 2013: 56 · 2012: 63
- FWCI
- 41.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Cancer Research UK (A8363)
- Topics
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Keywords
- BRCA2, intragenic deletion, PARP inhibitor resistance, platinum resistance, cisplatin, carboplatin, ovarian cancer, pancreatic cancer, homologous recombination, RAD51 foci, genomic instability, frameshift mutation, error-prone repair, BRCA2 mutation carriers
- MeSH terms
- Poly(ADP-ribose) Polymerase Inhibitors, Aged, Alleles, Amino Acid Sequence, Base Sequence, Chromosome Aberrations, Female, Fluorobenzenes, Humans, Middle Aged, Molecular Sequence Data, Mutation, Ovarian Neoplasms, Pancreatic Neoplasms, Phthalazines, Recombination, Genetic, Gene Expression Regulation, Neoplastic, Carboplatin, Open Reading Frames, Mitomycin, Sequence Deletion, Drug Resistance, Neoplasm, Genes, BRCA2, BRCA2 Protein, Cell Line, Tumor
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