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Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.

ABSTRACT: How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected mutations were found in 18 to 32% of normal skin cells at a density of ~140 driver mutations per square centimeter. We observed variability in the driver landscape among individuals and variability in the sizes of clonal expansions across genes. Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.

SUBMITTER: Martincorena I

PROVIDER: S-EPMC4471149 | biostudies-literature | 2015 May

REPOSITORIES: biostudies-literature

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Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.

Martincorena Iñigo I Roshan Amit A Gerstung Moritz M Ellis Peter P Van Loo Peter P McLaren Stuart S Wedge David C DC Fullam Anthony A Alexandrov Ludmil B LB Tubio Jose M JM Stebbings Lucy L Menzies Andrew A Widaa Sara S Stratton Michael R MR Jones Philip H PH Campbell Peter J PJ

Science (New York, N.Y.) 20150501 6237

How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultrav ...[more]

PMID: 25999502

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Project description:BackgroundCarcinogenesis typically involves multiple somatic mutations in caretaker (DNA repair) and gatekeeper (tumor suppressors and oncogenes) genes. Analysis of mutation spectra of the tumor suppressor that is most commonly mutated in human cancers, p53, unexpectedly suggested that somatic evolution of the p53 gene during tumorigenesis is dominated by positive selection for gain of function. This conclusion is supported by accumulating experimental evidence of evolution of new functions of p53 in tumors. These findings prompted a genome-wide analysis of possible positive selection during tumor evolution.MethodsA comprehensive analysis of probable somatic mutations in the sequences of Expressed Sequence Tags (ESTs) from malignant tumors and normal tissues was performed in order to access the prevalence of positive selection in cancer evolution. For each EST, the numbers of synonymous and non-synonymous substitutions were calculated. In order to identify genes with a signature of positive selection in cancers, these numbers were compared to: i) expected numbers and ii) the numbers for the respective genes in the ESTs from normal tissues.ResultsWe identified 112 genes with a signature of positive selection in cancers, i.e., a significantly elevated ratio of non-synonymous to synonymous substitutions, in tumors as compared to 37 such genes in an approximately equal-sized EST collection from normal tissues. A substantial fraction of the tumor-specific positive-selection candidates have experimentally demonstrated or strongly predicted links to cancer.ConclusionThe results of EST analysis should be interpreted with extreme caution given the noise introduced by sequencing errors and undetected polymorphisms. Furthermore, an inherent limitation of EST analysis is that multiple mutations amenable to statistical analysis can be detected only in relatively highly expressed genes. Nevertheless, the present results suggest that positive selection might affect a substantial number of genes during tumorigenic somatic evolution.

Project description:Viruses hijack cellular proteins, known as viral receptors, to initiate their infections. Viral receptors are subject to two conflicting directional forces, namely, negative selection to maintain their cellular function and positive selection resulted from the ever-changing host-virus arms race. Much remains unclear about how viral receptors evolved in mammals and whether viral receptors from different mammal groups experienced different strengths of natural selection. Here, we perform evolutionary analyses of 92 viral receptors in five major orders of mammals, including Carnivora, Cetartiodactyla, Chiroptera, Primates, and Rodentia. In all five mammal orders, signals of positive selection are detected for a high proportion of viral receptors (from 41% in Carnivora to 65% in Rodentia). Many positively selected residues overlap the host-virus interaction interface. Compared with control genes, we find viral receptors underwent elevated rates of adaptive evolution in all five mammal orders, suggesting that host-virus conflicts are the main driver of the adaptive evolution of viral receptors in mammals. Interestingly, the overall strength of natural selection acting on viral receptors driven by the host-virus arms race is largely homogenous and correlated among different mammal orders, with bats and rodents, zoonosis reservoirs of importance, being unexceptional. Taken together, our findings indicate host-virus conflicts have driven the elevated rate of adaptive evolution in viral receptors across mammals and might have important implications in zoonosis surveillance and prediction. IMPORTANCE Viral receptors are cellular proteins hijacked by viruses to help their infections. A complete picture on the evolution of viral receptors in mammals is still lacking. Here, we perform a comprehensive evolutionary analysis of the evolution of 92 viral receptors in five mammal orders, including Carnivora, Cetartiodactyla, Chiroptera, Primates, and Rodentia. We find that positive selection pervasively occurred during the evolution of viral receptors, and viral receptors exhibit an elevated rate of adaptive evolution compared to that of control genes in all five mammal orders, suggesting host-virus conflicts are a major driver of the adaptive evolution of viral receptors. Interestingly, the strength of positive selection acting on viral receptors is similar among the five mammal orders. Our study might have important implications in understanding the evolution of host-virus interaction.

Dataset Information

Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.

Publications

Tumor evolution. High burden and pervasive positive selection of somatic mutations in normal human skin.

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