Research Article

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

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Science  22 May 2015:
Vol. 348, Issue 6237, pp. 880-886
DOI: 10.1126/science.aaa6806

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Normal skin's curiously abnormal genome

Within every tumor, a battle is being waged. As individual tumor cells acquire new mutations that promote their survival and growth, they clonally expand at the expense of tumor cells that are “less fit.” Martincorena et al. sequenced 234 biopsies of sun-exposed but physiologically normal skin from four individuals (see the Perspective by Brash). They found a surprisingly high burden of mutations, higher than that of many tumors. Many of the mutations known to drive the growth of cutaneous squamous cell carcinomas were already under strong positive selection. More than a quarter of normal skin cells carried a driver mutation, and every square centimeter of skin contained hundreds of competing mutant clones.

Science, this issue p. 880; see also p. 867


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.

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