title: Clonal status of actionable driver events and the timing of mutational processes in cancer evolution.
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.
authors: Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Sciences and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK.
authors: Nicholas
authors: N
authors: McGranahan
authors: Cancer System Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark.
authors: Francesco
authors: F
authors: Favero
authors: UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley Street, London WC1E 6DD, UK.
authors: Elza C
authors: EC
authors: de Bruin
authors: Cancer Research UK London Research Institute, London WC2A 3LY, UK. Cancer System Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark. UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley Street, London WC1E 6DD, UK.
authors: Nicolai Juul
authors: NJ
authors: Birkbak
authors: Cancer System Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby 2800, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA.
authors: Zoltan
authors: Z
authors: Szallasi
authors: Cancer Research UK London Research Institute, London WC2A 3LY, UK. UCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Paul O'Gorman Building, Huntley Street, London WC1E 6DD, UK. charles.swanton@crick.ac.uk.
authors: Charles
authors: C
authors: Swanton
mesh_terms: D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D019656:Loss of Heterozygosity; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D057285:Precision Medicine; D015398:Signal Transduction; D013997:Time Factors