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Clinical brca1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance

Pettitt, SJ; Frankum, JR; Punta, M; Lise, S; Alexander, J; Chen, Y; Yap, TA; ... Lord, CJ; + view all (2020) Clinical brca1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance. Cancer Discovery , 10 (10) pp. 1475-1488. 10.1158/2159-8290.CD-19-1485. Green open access

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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 rever-sions 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.

Type: Article
Title: Clinical brca1/2 reversion analysis identifies hotspot mutations and predicted neoantigens associated with therapy resistance
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1158/2159-8290.CD-19-1485
Publisher version: https://doi.org/10.1158/2159-8290.CD-19-1485
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Amino Acid Sequence, BRCA1 Protein, BRCA2 Protein, Breast Neoplasms, Female, Homologous Recombination, Humans, Mutation
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: https://discovery.ucl.ac.uk/id/eprint/10175689
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