Dataset Information

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

ABSTRACT: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

SUBMITTER: de Bruin EC

PROVIDER: S-EPMC4636050 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

de Bruin Elza C EC McGranahan Nicholas N Mitter Richard R Salm Max M Wedge David C DC Yates Lucy L Jamal-Hanjani Mariam M Shafi Seema S Murugaesu Nirupa N Rowan Andrew J AJ Grönroos Eva E Muhammad Madiha A MA Horswell Stuart S Gerlinger Marco M Varela Ignacio I Jones David D Marshall John J Voet Thierry T Van Loo Peter P Rassl Doris M DM Rintoul Robert C RC Janes Sam M SM Lee Siow-Ming SM Forster Martin M Ahmad Tanya T Lawrence David D Falzon Mary M Capitanio Arrigo A Harkins Timothy T TT Lee Clarence C CC Tom Warren W Teefe Enock E Chen Shann-Ching SC Begum Sharmin S Rabinowitz Adam A Phillimore Benjamin B Spencer-Dene Bradley B Stamp Gordon G Szallasi Zoltan Z Matthews Nik N Stewart Aengus A Campbell Peter P Swanton Charles C

Science (New York, N.Y.) 20141001 6206

Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cy ...[more]

PMID: 25301630

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Project description:BackgroundStudies of biological shape evolution are greatly enhanced when framed in a phylogenetic perspective. Inclusion of fossils amplifies the scope of macroevolutionary research, offers a deep-time perspective on tempo and mode of radiations, and elucidates life-trait changes. We explore the evolution of skull shape in felids (cats) through morphometric analyses of linear variables, phylogenetic comparative methods, and a new cladistic study of saber-toothed cats.Methodology/principal findingsA new phylogenetic analysis supports the monophyly of saber-toothed cats (Machairodontinae) exclusive of Felinae and some basal felids, but does not support the monophyly of various saber-toothed tribes and genera. We quantified skull shape variation in 34 extant and 18 extinct species using size-adjusted linear variables. These distinguish taxonomic group membership with high accuracy. Patterns of morphospace occupation are consistent with previous analyses, for example, in showing a size gradient along the primary axis of shape variation and a separation between large and small-medium cats. By combining the new phylogeny with a molecular tree of extant Felinae, we built a chronophylomorphospace (a phylogeny superimposed onto a two-dimensional morphospace through time). The evolutionary history of cats was characterized by two major episodes of morphological divergence, one marking the separation between saber-toothed and modern cats, the other marking the split between large and small-medium cats.Conclusions/significanceAncestors of large cats in the 'Panthera' lineage tend to occupy, at a much later stage, morphospace regions previously occupied by saber-toothed cats. The latter radiated out into new morphospace regions peripheral to those of extant large cats. The separation between large and small-medium cats was marked by considerable morphologically divergent trajectories early in feline evolution. A chronophylomorphospace has wider applications in reconstructing temporal transitions across two-dimensional trait spaces, can be used in ecophenotypical and functional diversity studies, and may reveal novel patterns of morphospace occupation.

Dataset Information

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

Publications

Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.

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