How somatic mutations accumulate in normal cells is central to understanding cancer development, but is poorly understood. We performed ultra-deep sequencing of 74 cancer genes in small (0.8-4.7mm2) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged 2-6 mutations/megabase/cell, similar to many cancers, and exhibited characteristic signatures of ultraviolet light exposure. 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 ‘driver’ mutations were found in 18-32% of normal skin cells at a density of ~140/cm2. We observed variability in the driver landscape among individuals and variability in 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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机译：体细胞突变如何在正常细胞中积累是了解癌症发展的关键，但了解甚少。我们对正常皮肤的小（0.8-4.7mm 2 ）活检组织中的74个癌基因进行了超深度测序。在来自四个人的234次暴露于阳光下的眼睑表皮活检中，体细胞突变的负担平均为2-6个突变/兆碱基/细胞，与许多癌症相似，并且表现出紫外线暴露的特征性特征。值得注意的是，即使在生理上正常的皮肤中，包括大多数皮肤鳞状细胞癌的关键驱动因素，多种癌症基因也处于强阳性选择之下。在18-32％的正常皮肤细胞中发现了阳性选择的“驱动程序”突变，密度约为140 / cm 2 。我们观察到个体之间的驱动程序格局的变异性和跨基因克隆扩展大小的变异性。因此，老化，暴露在阳光下的皮肤是成千上万个不断进化的克隆的拼凑而成，超过四分之一的细胞带有致癌突变，同时又保持了表皮的生理功能。
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