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

By E. D. de Bruin, Nicholas McGranahan, R. Mitter, M. Salm, David C. Wedge, L. Yates, M. Jamal-Hanjani, S. Shafi, N. Murugaesu, A. Rowan and 33 more. Science, 2014

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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. Different regions of a human lung tumor harbor different mutations, possibly explaining why the disease is so tough to treat. [Also see Perspective by Govindan] Space, time, and the lung cancer genome Lung cancer poses a formidable challenge to clinical oncologists. It is often detected at a late stage, and most therapies work for only a short time before the tumors resume their relentless growth. Two independent analyses of the human lung cancer genome may help explain why this disease is so resilient (see the Perspective by Govindan). Rather than take a single “snapshot” of the cancer genome, de Bruin et al. and Zhang et al. identified genomic alterations in spatially distinct regions of single lung tumors and used this information to infer the tumor's evolutionary history. Each tumor showed tremendous spatial and temporal diversity in its mutational profiles. Thus, the efficacy of drugs may be short-lived because they destroy only a portion of the tumor. Science, this issue p. 251, p. 256; see also p. 169

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/81b2a6652a8fde71493fde504f0e7da1b55abf89

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In Pulmonary and Respiratory Medicine

Citations in the corpus

Biological and therapeutic impact of intratumor heterogeneity in cancer evolution. (2015, background): “Additionally, geographically distinct regions of the same tumor displayed different levels of APOBEC-mediated mutagenesis (de Bruin et al., 2014), suggesting drivers of diversity themselves can be both spatially heterogeneous and alter in dominance over time.”