果冻影院

Recently graduated CoMPLEX PhD student, Dr Nicholas McGranahan has recently published a paper that has been receiving a lot of interest in the press including from the听听补苍诲听.

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 鈥渁ctionable鈥� mutations, including听BRAF听(痴600贰),听IDH1听(搁132贬),听PIK3CA听(贰545碍),听EGFR听(L858R), and听KRAS听(G12D), which may compromise the efficacy of targeted therapy approaches. More than 20% of听IDH1听mutations in glioblastomas, and 15% of mutations in genes in the PI3K (phosphatidylinositol 3-kinase)鈥揂KT鈥搈TOR (mammalian target of rapamycin) signaling axis across all tumor types were subclonal. Mutations in the RAS鈥揗EK (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听CTNNA2听补苍诲听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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