Clonal status of actionable driver events and the timing of mutational processes in cancer evolution
Top Cited Papers
- 15 April 2015
- journal article
- research article
- Published by American Association for the Advancement of Science (AAAS) in Science Translational Medicine
- Vol. 7 (283), 283ra54
- https://doi.org/10.1126/scitranslmed.aaa1408
Abstract
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.Keywords
Funding Information
- Prostate Cancer Foundation
- Breast Cancer Research Foundation
- EU FP7 (259303)
- Cancer Research UK
- European Research Council (THESEUS)
- Rosetrees Trust
This publication has 43 references indexed in Scilit:
- Mechanisms underlying mutational signatures in human cancersNature Reviews Genetics, 2014
- Discovery and saturation analysis of cancer genes across 21 tumour typesNature, 2014
- Widespread Genetic Heterogeneity in Multiple Myeloma: Implications for Targeted TherapyCancer Cell, 2014
- Mutational landscape and significance across 12 major cancer typesNature, 2013
- The causes and consequences of genetic heterogeneity in cancer evolutionNature, 2013
- Signatures of mutational processes in human cancerNature, 2013
- Evolution of the cancer genomeNature Reviews Genetics, 2012
- Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancerNature, 2012
- Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor responseProceedings of the National Academy of Sciences, 2012
- Mosaic Amplification of Multiple Receptor Tyrosine Kinase Genes in GlioblastomaCancer Cell, 2011