Clonal status of actionable driver events and the timing of mutational processes in cancer evolution
Open accessAbstract
Deciphering whether actionable driver mutations are found in all or a subset of tumor cells will likely be required to improve drug development and precision medicine strategies. We analyzed nine cancer types to determine the subclonal frequencies of driver events, to time mutational processes during cancer evolution, and to identify drivers of subclonal expansions. Although mutations in known driver genes typically occurred early in cancer evolution, we also identified later subclonal "actionable" mutations, including BRAF (V600E), IDH1 (R132H), PIK3CA (E545K), EGFR (L858R), and KRAS (G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of IDH1 mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)-AKT-mTOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS-MEK (mitogen-activated protein kinase kinase) signaling axis were less likely to be subclonal than mutations in genes associated with PI3K-AKT-mTOR signaling. Analysis of late mutations revealed a link between APOBEC-mediated mutagenesis and the acquisition of subclonal driver mutations and uncovered putative cancer genes involved in subclonal expansions, including CTNNA2 and ATXN1. Our results provide a pan-cancer census of driver events within the context of intratumor heterogeneity and reveal patterns of tumor evolution across cancers. The frequent presence of subclonal driver mutations suggests the need to stratify targeted therapy response according to the proportion of tumor cells in which the driver is identified.
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KRAS mutations can occur both clonally or subclonally in NSCLC.
“KRAS mutations can occur both clonally or subclonally in NSCLC, 21”
From K-ras Mutation Subtypes in NSCLC and Associated Co-occuring Mutations in Other Oncogenic Pathways (2019) · cites this paper as [21]
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- Authors
- McGranahan, N., Favero, F., de Bruin, E. C., Birkbak, N. J., Szallasi, Z., & Swanton, C.
- Affiliations
- Cancer Research UK (GB)
- Technical University of Denmark (DK)
- UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O’Gorman Building, Huntley Street, London WC1E 6DD, UK.
- Cancer System Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark.
- Corresponding author
- McGranahan, Nicholas
- Birkbak, Nicolai Juul
- Swanton, Charles
- Venue
- Science Translational Medicine
- Published
- 2015-04-15
- Volume
- 7
- Issue
- 283
- Pages
- 283ra54-283ra54
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- OpenAlex
- W2154974159
- Cited by
- 685
- References
- 45
- Citations by year
- 2026: 23 · 2025: 23 · 2024: 45 · 2023: 51 · 2022: 84 · 2021: 83 · 2020: 96 · 2019: 63 · 2018: 75 · 2017: 70 · 2016: 47 · 2015: 23
- FWCI
- 23.70
- Type
- journal article
- Language
- en
- Open access
- green
- figshare.com
- Locations
- Science Translational Medicine (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Technical University of Denmark, DTU Orbit (Technical University of Denmark, DTU) (submittedVersion)
- Funders
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- EU FP7 (259303)
- Cancer Research UK
- European Research Council (THESEUS)
- Rosetrees Trust
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- actionable driver mutations, intratumoral heterogeneity, tumor evolution, mutational processes, PI3K/AKT/mTOR pathway, APOBEC mutagenesis, subclonal expansion, BRAF V600E mutation, IDH1 R132H mutation, PIK3CA E545K, L858R mutation, KRAS G12D, glioblastoma, targeted therapy response, CTNNA2, ataxin-1
- MeSH terms
- DNA Mutational Analysis, Humans, Mutation, Neoplasms, Time Factors, Signal Transduction, Genome, Human, Gene Expression Regulation, Neoplastic, Gene Dosage, Loss of Heterozygosity, Oligonucleotide Array Sequence Analysis, Genomics, Cell Line, Tumor, Precision Medicine
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