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Seeds of cancer in normal skin

Sequencing the genomes of individual skin cells called melanocytes has revealed a rich landscape of DNA changes. These insights shed light on the origins of melanoma, an aggressive type of cancer.
Inigo Martincorena is at the Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
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Mutations occur in our cells throughout life. Although most mutations are harmless, they accumulate in number in our tissues as we age, and if they arise in key genes, they can alter cellular behaviour and set cells on a path towards cancer. There is also speculation that somatic mutations (those in non-reproductive tissues) might contribute to ageing and to diseases unrelated to cancer. However, technical difficulties in detecting the mutations present in a small number of cells, or even in single cells, have hampered research and limited progress in understanding the first steps in cancer development and the impact of somatic mutation on ageing and disease. Writing in Nature, Tang et al.1 report work that overcame some of these experimental limitations to explore somatic mutations and selection in individual melanocytes — the type of skin cell that can give rise to the cancer melanoma.

The epidermis is the skin’s outermost layer. Just 0.1 millimetres thick, the epidermis is battered by mutation-promoting ultraviolet rays over a person’s lifetime, and is the origin of the vast majority of skin cancers.

To understand the extent of somatic mutation in a human tissue, and the origin of skin cancers, a previous study2 used DNA sequencing of small biopsies of normal epidermis. This revealed not only that mutations are common in normal cells, but also that mutations in cancer-promoting genes favour the growth of small groups of mutant cells (clones) that progressively colonize our skin as we age. However, the sequencing of biopsies of epidermis made up of thousands of cells mostly detected mutations in cells called keratinocytes, which comprise around 90% of all cells in the epidermis3. These are the cells from which the common, but typically treatable, non-melanoma skin cancers develop. The origins of melanoma, a rarer but more lethal form of skin cancer, lie in single cells scattered throughout the skin, called melanocytes (Fig. 1). These cells produce a pigment called melanin that gives skin its colour and protects it from the onslaught of sun damage.

Figure 1

Figure 1 | Identifying mutations in human skin cells. a, Tang et al.1 analysed a type of cell called a melanocyte, which is present at the base of the skin’s outer layer (termed the epidermis). Cancer-promoting mutations in melanocytes can lead to the formation of a lethal cancer known as melanoma. Studying mutations in these cells is difficult because the cells are rare compared with another type of epidermal cell, called a keratinocyte. b, The authors obtained biopsied samples of human skin, and isolated individual melanocyte cells from healthy individuals and from people with skin cancer. After growing individual cells in vitro to obtain colonies of cells, Tang and colleagues used the method of whole-genome amplification, and sequenced DNA. To determine whether the possible mutations identified were genuine or the result of sequencing errors, the authors compared DNA and RNA sequencing results corresponding to the same genetic region to check whether the results matched.

To detect mutations in melanocytes, Tang et al. had to devise reliable ways to sequence the DNA of single cells. Two main approaches have been used for other cell types: single-cell sequencing, which relies on error-prone, whole-genome amplification4; and growing single cells into colonies of thousands of cells in a dish, which enables the use of more-reliable sequencing methods5,6. The former approach introduces many errors per cell that can be mistaken for genuine mutations, whereas the latter method is restricted in use to cells that grow well in vitro. Melanocytes are difficult to grow into large colonies of cells in vitro, so Tang et al. combined the two approaches, growing single melanocytes in vitro into colonies of tens to hundreds of cells; only then did they undertake the whole-genome amplification step, thus minimizing DNA sequencing errors.

Through a series of clever analyses and controls, which included sequencing DNA and RNA from each colony to confirm certain mutations, the authors could reliably detect somatic mutations found in single melanocytes. The accuracy of the results was also helped by the fact that skin cells, including melanocytes, have much higher mutation rates than the rates of other cells in the body6, minimizing the confounding effect of sequencing errors arising from the amplification approach.

Tang et al. sequenced key parts of the genomes of cellular colonies derived from 133 individual melanocytes, collected from 19 body sites in 6 deceased donors. The donors included two people with skin cancer, as well as cancer-free individuals. They were all of European ancestry, and their ages ranged from 63 to 85 years. Although the modest sample size is a limitation of the study, the biological insights from this technical tour de force are remarkable.

Reassuringly, the vast majority of mutations detected had the expected characteristic signature of DNA alterations associated with ultraviolet damage. The number of mutations per melanocyte varied widely across donors and body sites, with an average of around 20,000 mutations per cell in sun-exposed areas, which is approximately similar to the number of mutations found in melanomas2. An unexpected observation is that chronically sun-exposed skin (on the face, for example) had lower numbers of mutations than did intermittently sun-exposed skin (in areas such as the thigh or back). The authors speculate that this finding could explain why most melanomas occur in intermittently sun-exposed areas, although further analysis, using more donors, will be needed to confirm this observation.

A second finding, which was even more unexpected, is that some melanocytes in sun-exposed tissues had many fewer mutations than did other melanocytes in the same biopsy sample. The origin of these cells is unclear. One possibility is that they previously resided in a site safe from sun damage, such as a hair follicle, that provided a protected niche. Tang and colleagues’ observation of a population of seemingly ‘protected’ cells among highly mutated cells is reminiscent of the discovery7 that some lung cells in ex-smokers do not have characteristic tobacco-induced mutations, and that these cells might even slowly replace the lung cells damaged by years of smoking. Future studies to investigate melanocytes with surprisingly low numbers of mutations will be of interest to understand the origin and function of such cells.

By analysing genes involved in the development of melanoma, Tang et al. found that around 20% of melanocytes had one melanoma-driving mutation (occasionally, some cells had two such driver mutations). Interestingly, the authors observed that these mutations can lead to melanocyte growth that results in ‘scattered fields’ of mutant melanocytes, as suggested by evidence that some melanocytes obtained from the same biopsy shared the same driver mutations. In the past few years, studies of several tissues2,8,9 have reported similar observations of mutations in cancer-driving genes promoting the growth of cells to form mutant clones. This previously unknown phenomenon is emerging as a common feature of ageing across multiple tissues.

The cancer-promoting mutations in melanocytes found by Tang and colleagues occurred mainly in well-documented melanoma-promoting genes that activate the MAPK signalling pathway, such as BRAF and NRAS. Remarkably, the two most-common mutations in melanoma (a mutation termed BRAFV600E and mutation of the regulatory promoter region of the TERT gene)10 are absent from the list. To explain this conundrum, the authors propose that melanomas emerge from two main routes. Either they arise from existing moles in the skin, which often have the BRAFV600E mutation, or they form de novo without a pre-existing mole. The cancer-driving mutations found by the authors in scattered melanocytes might therefore represent the origins of some de novo melanomas.

This carefully conducted study offers an unprecedented view of the landscape of somatic mutations in normal melanocytes, providing new clues about the origins of melanoma and presenting many intriguing observations that should motivate further research. Together with similar efforts in other tissues, studies such as this one by Tang and colleagues are rapidly changing our understanding of somatic mutations in normal tissues and the relevance of these mutations for health and disease.

Nature 586, 504-506 (2020)

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