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ScienceWeek
MEDICAL BIOLOGY: IMMUNOSUPPRESSION AND SKIN CANCER
The following points are made by John A. Parrish (New Engl. J. Med. 2005 353:2712):
1) Skin cancer is a serious problem in immunosuppressed patients. In these patients, cutaneous cancers are common in areas of the skin that are exposed to the sun, are more aggressive than in patients who are not immunosuppressed, are sometimes fatal, and often require multiple surgical procedures.[1] Although the absolute risk of squamous-cell carcinoma after renal transplantation is highest in sunny climates, the risk of these tumors is also greatly elevated in less sunny areas. For example, a study of more than 700 renal-transplant recipients in the Netherlands disclosed that the overall incidence of squamous-cell carcinoma was 250 times that in the general Dutch population.[2] The reasons for the dramatic increase in these tumors among immunosuppressed patients is not completely understood, although it is often attributed to decreased cancer surveillance owing to panimmunosuppression that results from drug therapy and exposure to ultraviolet B (UVB) radiation. A recent study by O'Donovan and colleagues, however, points a finger elsewhere: they show that azathioprine, an immunosuppressant used in organ transplantation, sensitizes DNA to ultraviolet A (UVA) radiation.[3]
2) UVA radiation comprises more than 90 percent of incident midday solar ultraviolet radiation and is present for more hours of each day and throughout the year than UVB radiation. It penetrates more deeply into skin than UVB, and it passes through glass. O'Donovan et al[3] showed that treatment with azathioprine causes 6-thioguanine (the active metabolite of azathioprine) to be incorporated into the DNA of patients' skin cells. On exposure to low levels of UVA radiation, this metabolite is converted in an oxygen-dependent reaction into two products that are bad news for DNA: reactive oxygen species and guanine-6-sulfonate (G-6-SO3). A sudden increase in reactive oxygen species causes oxidative stress, which in turn produces DNA lesions. O'Donovan et al[3] also showed that G-6-SO3 itself is mutagenic.
3) These observations are consistent with the results of another experiment this group conducted to evaluate the extent to which exposure to a low level of UVA radiation, cell culture with 6-thioguanine, and the two combined to increase the number of mutations in a reporter gene. They found that neither agent on its own detectably increases the number of mutations, but the two combined result in a threefold increase, as compared with the control. Thus, 6-thioguanine photosensitizes cells to UVA radiation.
4) Whether these findings are relevant to the incidence of squamous-cell carcinoma in patients treated with azathioprine has yet to be determined, although the authors provided a relevant finding. They compared the minimal erythema dose (the minimal amount of radiation required to elicit erythema) in patients before and three months after the initiation of therapeutic doses of azathioprine and found that with treatment, the skin became more sensitive to UVA but not UVB radiation.[4,5]
References (abridged):
1. Berg D, Otley CC. Skin cancer in organ transplant recipients: epidemiology, pathogenesis, and management. J Am Acad Dermatol 2002;47:1-17
2. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation 1990;49:506-509
3. O'Donovan P, Perrett CM, Zhang X, et al. Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 2005;309:1871-1874
4. Stern RS, Laird N, Melski J, Parrish JA, Fitzpatrick TB, Bleich HL. Cutaneous squamous-cell carcinoma in patients treated with PUVA. N Engl J Med 1984;310:1156-1161
5. Marcil I, Stern R. Squamous-cell cancer of the skin in patients given PUVA and ciclosporin: nested cohort crossover study. Lancet 2001;358:1042-1045
New Engl. J. Med. http://www.nejm.org
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Related Material:
SKIN CANCERS AND ORGAN TRANSPLANTATION
The following points are made by S. Euvrard et al (New Engl. J. Med. 2003 348:1681):
1) Long-term survival after organ transplantation is increasing. As a result, many patients have long-term complications of transplantation. Adequate graft function requires lifelong immunosuppressive treatment, and the resultant modification of the immune system is associated with an increased risk of various cancers, particularly those involving viruses. Skin cancers are the most common malignant conditions in transplant recipients and account for substantial morbidity and mortality in such patients.
2) Squamous-cell and basal-cell carcinomas account for more than 90 percent of all skin cancers in transplant recipients. The incidence of these carcinomas increases with the duration of immunosuppressive therapy, ultimately affecting 50 percent or more of white transplant recipients. For example, the cumulative incidence of skin cancer in transplant recipients in Queensland, Australia, increases from 7 percent after 1 year of immunosuppressive therapy to 82 percent after 20 years. Among Dutch transplant recipients, the incidence of skin cancer at one year is 0.2 percent and the long-term incidence is 41 percent.
3) Squamous-cell carcinoma is the most common skin cancer in transplant recipients, occurring 65 to 250 times as frequently as in the general population. The incidence of basal-cell carcinomas is reportedly increased by a factor of 10 in transplant recipients. The risk appears to increase linearly for basal-cell carcinomas and exponentially for squamous-cell carcinomas; thus, the ratio of squamous-cell to basal-cell carcinomas in patients without transplants (1:4) is reversed in transplant recipients. The relative risk of squamous-cell carcinoma after transplantation is higher for men than for women, except for cancers of the lip. Curiously, skin cancers appear to be extremely rare in Japanese patients with transplants.
New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek:
The skin cancer called "basal-cell carcinoma", rare in Blacks and Asians, is the most common malignant skin tumor in Whites. This cancer arises from the undifferentiated basal keratinocytes of the epidermis. Such cancers rarely metastasize but may be highly invasive locally, when they are called "rodent ulcers". The lesions are prevalent in fair-skinned persons and on areas of skin that receive the greatest exposure to sunlight. Treatment with inorganic arsenical drugs and exposure to ionizing radiation (e.g., x-rays) may also be contributing factors.
The skin cancer called "squamous-cell carcinoma" is less common than basal-cell carcinoma but has a higher rate of metastasis. Squamous-cell carcinoma is common in children with xeroderma pigmentosum, who are unable to repair DNA damage caused by ultraviolet radiation. In most persons, such an inability to repair DNA damage is due to a deficiency of an endonuclease enzyme. In adults, squamous-cell carcinoma rarely occurs in the absence of an external cause, and protracted exposure to sunlight is the usual cause of this disease. Chronic scarring from burns, as well as reactions to vaccinations, radiation dermatitis, and chronic ulceration may also be risk factors for squamous-cell carcinoma of the skin.
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MEDICAL BIOLOGY: PATHOGENESIS OF UV INDUCTION OF MELANOMAS
Notes by ScienceWeek:
Skin cancers, predominantly *basal-cell and *squamous-cell *carcinomas, have accounted for an estimated 40 percent of all cancers in the US in recent years, and the frequency of these cancers has been increasing. The most common fatal skin cancer is *melanoma, and this has also increased, indeed by a factor of approximately 15 in the past 60 years. In 1997, more than 40,000 new cases of melanoma were diagnosed in the US, with more than 7200 fatalities.
The following points are made by B.A. Gilchrest et al (New Engl. J. Med. 1999 340:1341):
1) The factors underlying the rapid increase in the incidence of skin cancer are incompletely understood, but increased total exposure to the Sun, and in the case of melanoma, altered patterns of exposure, are strongly implicated.
2) The risk of melanoma is higher in fair-skinned people, especially those with blond or red hair who sunburn and freckle easily, than in people with darker complexions. The incidence of melanoma among whites is inversely related to the latitude of residence, with the world's highest incidence in Australia, a subtropical country with a largely Celtic population. Conversely, melanomas are uncommon in darker-skinned people.
3) The epidemiologic evidence implicating solar exposure in the causation of melanoma is supported by biologic evidence that damage caused by ultraviolet radiation, particularly damage to DNA, plays a central part in the pathogenesis of these tumors.
4) Age plays a major part in vulnerability to photocarcinogenesis. Aging (the passage of time) provides more opportunities for the initiation of tumor formation (the induction of mutations by exposure to UV radiation) and for the promotion of tumor formation (the reparative cell proliferation after exposure to UV radiation or after other skin injury). There is an age-associated decrease in the capacity to repair DNA, and a consequent increase in the rate of mutations of DNA. Moreover, the rate of removal of UV-radiation-induced DNA photoproducts from UV-irradiated skin decreases with age, especially during the first two decades of life.
5) There has been considerable research addressing the relative contributions of UV-B wavelengths (290-320 nm) and UV-A wavelengths (320-400 nm) to photocarcinogenesis, particularly to the development of melanoma. UV-B radiation is overwhelmingly responsible for the formation of the principle DNA lesions, cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts, whose incorrect repair leads to mutations. However, UV-A radiation is far more abundant in sunlight than UV-B radiation, and UV-A radiation causes oxidative DNA damage that is also potentially mutagenic. UV-A radiation is also believed to contribute substantially to immunosuppression, thus preventing immunologic rejection of nascent UV-induced skin cancers.
6) Unlike the more common skin cancers, which are associated with total cumulative exposure to UV radiation, melanomas are associated with intense intermittent exposure. Thus, basal-cell and squamous-cell carcinomas occur most commonly in maximally solar-exposed areas of the body (e.g., face, back of hands, forearms, and in persons with almost daily and substantial lifetime exposure to UV radiation, such as farmers and sailors). In contrast, melanoma occurs most commonly in areas of the body exposed to the Sun intermittently, such as the back in men and the lower legs in women, with relative sparing of more frequently exposed sites such as the face, hands, and forearms. Melanoma is most common in persons with predominantly indoor occupations whose exposure to the Sun is limited to weekends and vacations. Indeed the large increase in the incidence of melanoma in recent decades has been attributed in part to the ability of large numbers of people to travel long distances to obtain intense exposure to the Sun in winter.
7) The authors propose a hypothesis to explain the epidemiology of melanoma as compared with non-melanoma skin cancer, the authors suggesting that the data predict that a high-dose first exposure to the Sun after a prolonged period of Sun avoidance will cause substantial damage to DNA in *melanocytes and *keratinocytes, both of which at that time have a relatively low base-line capacity for DNA repair and a low melanin content. The authors propose that the final effect of UV radiation is not attributable simply to the cumulative dose -- the arithmetic sum of all individual exposures over a lifetime -- but rather may be strongly influenced by the dose per exposure and by the pattern of exposures.
8) The authors conclude: "Protection from the Sun is critical to the prevention of both melanoma and non-melanoma skin cancers, and protection is most effective when it is begun in early childhood. It is especially important to protect against intermittent Sun exposures, in order to reduce genomic damage at a time of maximal cellular vulnerability and to reduce the risk of melanoma."
New Engl. J. Med. http://www.nejm.org
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Notes by ScienceWeek:
basal-cell: A basal cell is a cell of the deepest layer of stratified epithelium. In animals, including humans, epithelial cells (epithelium) compose the cell layers that form the interface between a tissue and the external environment, for example, the cells of the skin, the lining of the intestinal tract, and the lung airway passages. The term "stratified epithelium" is a general term for epithelium composed of several layers of different cell types.
squamous-cell: The cells of the epithelium are for the most part closely packed cells with little extracellular material between adjacent cells, the cells arranged in continuous sheets in either single or multiple layers. The cells may be flat, cube-like, columnar, or a combination of shapes, and "squamous" cells are flattened and scale-like.
carcinomas: In general, a carcinoma is any malignancy derived from epithelial tissue.
melanoma: Melanomas are a group of skin cancers involving *melanocytes, cells found throughout the lower layers of the skin.
melanocytes: (melanodendrocytes) Pigment-producing cells located in the deepest (basal) layer of the skin (epidermis) with branching processes by means of which melanin-containing bodies (melanosomes) are transferred to epidermal cells with a resultant pigmentation of the epidermis.
keratinocytes: "Keratinocyte" is a generic term for any mammalian epithelial cell that produces keratin, a group of proteins present in cuticular structures (e.g., hair, nails).
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