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dc.contributor.authorPettitt, SJ
dc.contributor.authorFrankum, JR
dc.contributor.authorPunta, M
dc.contributor.authorLise, S
dc.contributor.authorAlexander, J
dc.contributor.authorChen, Y
dc.contributor.authorYap, TA
dc.contributor.authorHaider, S
dc.contributor.authorTutt, ANJ
dc.contributor.authorLord, CJ
dc.date.accessioned2020-09-16T13:27:39Z
dc.date.issued2020-10-01
dc.identifier.citationCancer discovery, 2020, 10 (10), pp. 1475 - 1488
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4069
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.cd-19-1485
dc.description.abstractReversion 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.
dc.formatPrint-Electronic
dc.format.extent1475 - 1488
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
dc.titleClinical BRCA1/2 Reversion Analysis Identifies Hotspot Mutations and Predicted Neoantigens Associated with Therapy Resistance.
dc.typeJournal Article
dcterms.dateAccepted2020-07-01
rioxxterms.versionofrecord10.1158/2159-8290.cd-19-1485
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/under-embargo-all-rights-reserved
rioxxterms.licenseref.startdate2020-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer discovery
pubs.issue10
pubs.notesNo embargo
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Gene Function
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Gene Function
pubs.publication-statusPublished
pubs.volume10
pubs.embargo.termsNo embargo
icr.researchteamGene Function
dc.contributor.icrauthorPettitt, Stephen
dc.contributor.icrauthorLise, Stefano
dc.contributor.icrauthorHaider, Syed
dc.contributor.icrauthorTutt, Andrew
dc.contributor.icrauthorLord, Christopher


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