How important are somatic mutations and immune control in skin cancer? Reflections on xeroderma pigmentosum

One of the key pieces of evidence in favour of the somatic mutation theory of cancer comes from the hereditary disease xeroderma pigmentosum (XP). Cells from such patients are deficient in the repair of DNA damage caused by a wide variety of mutagens including far u.v. light (FUV) and photochemical sensitization by psoralens and near u.v. light (PUVA). The cells, in consequence, are killed or mutated by doses very much lower than those required for cells from normal individuals. XP individuals themselves show a high incidence of skin tumours on areas of skin exposed to light, which is commonly said to reflect the relative hypersensitivity to sunlight-induced mutation to malignancy, (i.e., initiation), in cells of the skin. This has been an attractive interpretation but I suggest it may be an oversimplification, at least when viewed quantitatively. Should not one also take into account the likelihood that skin cancer (particularly squamous cell carcinoma) rarely appears except when normal control processes in the skin are impaired. It is well known, for example, that skin cancer is common in patients undergoing strong immunosuppressive therapy (1) implying that potentially malignant cells are present in normal skin more often than is generally realized and suggesting that some sort of immune process normally plays a role in controlling their growth into overt neoplasms. Earlier, Dupuy and Lafforet (2) had found evidence for impaired cell-mediated immunity (including an inability to obtain sensitization to dinitrochlorobenzene) in XP patients and hypothesized that this might contribute to their proneness to develop skin cancer. Subsequently, Bridges and Strauss (3) discussed evidence that DNA damage such as that produced by FUV and PUVA can cause breakdown of immune control in the skin of animals. They suggested that the elevated rate of squamous cell carcinoma observed in psoriasis patients undergoing recent PUVA therapy (4) might be attributable to such an effect rather than to mutation, since squamous cell carcinomas, at least within the first 2 years after commencement of PUVA