Mutational signatures impact the evolution of anti-EGFR antibody resistance in colorectal cancer.
Date
2021-05-20Author
Woolston, A
Barber, LJ
Griffiths, B
Pich, O
Lopez-Bigas, N
Matthews, N
Rao, S
Watkins, D
Chau, I
Starling, N
Cunningham, D
Gerlinger, M
Type
Journal Article
Metadata
Show full item recordAbstract
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.
Collections
Research team
Medicine (RMH Smith Cunningham)
Translational Oncogenomics
Medicine (RMH Smith Cunningham)
Translational Oncogenomics
Language
eng
Date accepted
2021-04-20
License start date
2021-04-20
Citation
Nature Ecology and Evolution
Publisher
NATURE PORTFOLIO