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

By Iñigo Martincorena, A. Roshan, Moritz Gerstung, P. Ellis, P. van Loo, Stuart McLaren, David C. Wedge, A. Fullam, Ludmil B. Alexandrov, J. Tubío and 6 more. Science, 2015

1,462 citations recorded by the source corpus.

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 Sun-exposed but physiologically normal human skin harbors an unexpectedly high number of cancer-causing mutations. [Also see Perspective by Brash] 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.

Subfields: Cancer Research, Dermatology, Oncology

View Paper: https://www.semanticscholar.org/paper/96511e6b1a6e0a231f08e933becd20687ca9c41d

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Citations in the corpus

The Human Cell Atlas (2017, background): “…DNA changes (such as somatic point mutations, or repeat expansions at microsatellite loci) at each cell division (Behjati et al., 2014; Biezuner et al., 2016; Martincorena et al., 2015; Reizel et al., 2012; Shlush et al., 2012) or as a molecular clock (Taylor et al., 2003; Teixeira et al., 2013).”
Somatic mutation in single human neurons tracks developmental and transcriptional history (2015, result): “These rates are in agreement with previous estimates of the somatic SNV rate obtained using single-cell sequencing, ultra-deep sequencing of normal cells, and analysis of LOH events in normal cells that lead to tumorigeneisis (11-14).”
Early detection of cancer (2022, positive): “However, it is increasingly clear that phenotypically normal tissue also harbors a range of somatic mutations that might normally be considered indicative of cancer or to be drivers of cancer genesis (67).”
Revisiting the hallmarks of cancer. (2017, positive): “This is backed up by findings such as clonal hematopoiesis in aged individuals [213] and high mutational burden in aged skin cells [10], both harboring driver mutations of malignant transformation, perhaps just a few steps away.”
OncodriveFML: a general framework to identify coding and non-coding regions with cancer driver mutations (2016, background): “…we analyzed the list of somatic mutations detected in a panel of genes sequenced at high coverage across 234 biopsies of sun-exposed epidermis [38] to illustrate the use of OncodriveFML on the task of detecting genes under positive selection in the case when most mutations in the sample are…”
Clonal hematopoiesis in human aging and disease (2019, positive): “An equivalent state is also pervasive in the epithelium of skin (15) and esophagus (16, 17), suggesting that somatic mutation–driven clonal expansions may be a characteristic of aging in several tissues.”