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Clinical <i>BRCA1/2</i> Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance.

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Date
2020-10
ICR Author
Haider, Syed
Lise, Stefano
Lord, Christopher
Pettitt, Stephen
Author
Pettitt, SJ
Frankum, JR
Punta, M
Lise, S
Alexander, J
Chen, Y
Yap, TA
Haider, S
Tutt, ANJ
Lord, CJ
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Type
Journal Article
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Abstract
Reversion mutations in BRCA1 or BRCA2 are associated with resistance to PARP inhibitors and platinum. To better understand the nature of these mutations, we collated, codified, and analyzed more than 300 reversions. This identified reversion "hotspots" and "deserts" in regions encoding the N and C terminus, respectively, of BRCA2, suggesting that pathogenic mutations in these regions may be at higher or lower risk of reversion. Missense and splice-site pathogenic mutations in BRCA1/2 also appeared less likely to revert than truncating mutations. Most reversions were <100 bp deletions. Although many deletions exhibited microhomology, this was not universal, suggesting that multiple DNA-repair processes cause reversion. Finally, we found that many reversions were predicted to encode immunogenic neopeptides, suggesting a route to the treatment of reverted disease. As well as providing a freely available database for the collation of future reversion cases, these observations have implications for how drug resistance might be managed in BRCA -mutant cancers. SIGNIFICANCE: Reversion mutations in BRCA genes are a major cause of clinical platinum and PARP inhibitor resistance. This analysis of all reported clinical reversions suggests that the position of BRCA2 mutations affects the risk of reversion. Many reversions are also predicted to encode tumor neoantigens, providing a potential route to targeting resistance. This article is highlighted in the In This Issue feature, p. 1426 .
URI
https://repository.icr.ac.uk/handle/internal/4069
DOI
https://doi.org/10.1158/2159-8290.cd-19-1485
Collections
  • Breast Cancer Research
  • Molecular Pathology
Research team
Gene Function
Language
eng
Date accepted
2020-07-01
License start date
2020-10
Citation
Cancer discovery, 2020, 10 (10), pp. 1475 - 1488

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