dc.contributor.author | Woolston, A | |
dc.contributor.author | Barber, LJ | |
dc.contributor.author | Griffiths, B | |
dc.contributor.author | Pich, O | |
dc.contributor.author | Lopez-Bigas, N | |
dc.contributor.author | Matthews, N | |
dc.contributor.author | Rao, S | |
dc.contributor.author | Watkins, D | |
dc.contributor.author | Chau, I | |
dc.contributor.author | Starling, N | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Gerlinger, M | |
dc.date.accessioned | 2021-04-20T13:32:20Z | |
dc.date.accessioned | 2021-05-14T10:29:28Z | |
dc.date.available | 2021-05-14T10:29:28Z | |
dc.date.issued | 2021-05-20 | |
dc.identifier.citation | Nature Ecology and Evolution | |
dc.identifier.issn | 2397-334X | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4555 | |
dc.description.abstract | Anti-EGFR antibodies such as cetuximab are active against KRAS/NRAS wild-type colorectal cancers (CRCs), but acquired resistance invariably evolves. It is unknown which mutational mechanisms enable resistance evolution and whether adaptive mutagenesis (a transient cetuximab-induced increase in mutation generation) contributes in patients. Here, we investigate these questions in exome sequencing data from 42 baseline and progression biopsies from cetuximab-treated CRCs. Mutation loads did not increase from baseline to progression, and evidence for a contribution of adaptive mutagenesis was limited. However, the chemotherapy-induced mutational signature SBS17b was the main contributor of specific KRAS/NRAS and EGFR driver mutations that are enriched at acquired resistance. Detectable SBS17b activity before treatment predicted shorter progression-free survival and the evolution of these specific mutations during subsequent cetuximab treatment. This result suggests that chemotherapy mutagenesis can accelerate resistance evolution. Mutational signatures may be a new class of cancer evolution predictor. | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | NATURE PORTFOLIO | |
dc.relation.replaces | https://repository.icr.ac.uk/handle/internal/4525 | |
dc.relation.replaces | internal/4525 | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-04-20 | |
rioxxterms.version | AM | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2021-04-20 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Nature Ecology and Evolution | |
pubs.notes | Not known | |
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/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
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/Clinical Studies | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.) | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Translational Oncogenomics | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Accepted | |
pubs.embargo.terms | Not known | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Translational Oncogenomics | |
icr.researchteam | Medicine (RMH Smith Cunningham) | |
icr.researchteam | Translational Oncogenomics | |
dc.contributor.icrauthor | Woolston, Andrew | |
dc.contributor.icrauthor | Gerlinger, Marco | |