High Incidence Of Skin Cancer Research Articles

Yeast DNA-repair gene RAD14 encodes a zinc metalloprotein with affinity for ultraviolet-damaged DNA.

Xeroderma pigmentosum (XP) patients suffer from a high incidence of skin cancers due to a defect in excision repair of UV light-damaged DNA. Of the seven XP complementation groups, A-G, group A represents a severe and frequent form of the disease. The Saccharomyces cerevisiae RAD14 gene is a homolog of the XP-A correcting (XPAC) gene. Like XP-A cells, rad14-null mutants are defective in the incision step of excision repair of UV-damaged DNA. We have purified RAD14 protein to homogeneity from extract of a yeast strain genetically tailored to overexpress RAD14. As determined by atomic emission spectroscopy, RAD14 contains one zinc atom. We also show in vitro that RAD14 binds zinc but does not bind other divalent metal ions. In DNA mobility-shift assays, RAD14 binds specifically to UV-damaged DNA. Removal of cyclobutane pyrimidine dimers from damaged DNA by enzymatic photoreactivation has no effect on binding, strongly suggesting that RAD14 recognizes pyrimidine(6-4)pyrimidone photoproduct sites. These findings indicate that RAD14 functions in damage recognition during excision repair.

Skin cancer and chromosomal aberrations induced by ultraviolet radiation: Evidence for lack of correlation in xeroderma pigmentosum variant and group E patients

Ultraviolet radiation (UV) in sunlight induces an abnormally high incidence of skin cancer in patients with xeroderma pigmentosum (XP), an autosomal recessive disease with defects in the repair of damaged DNA. We determined the frequency of UV-induced chromosomal aberrations in cultured lymphoblast lines from a patient with the variant form of XP, from a patient with the complementation group E form, and from two patients with the complementation group C form. In contrast to results with patients having other forms of XP, the group E and variant patients showed no abnormal increase in UV-induced chromosomal aberrations. Even in the presence of caffeine, which exacerbates the postreplication repair defect of UV-irradiated XP variant cells, there was still no abnormally elevated frequency of UV-induced chromosomal aberrations in the variant cells. These results, indicating that the level of UV-induced chromosomal aberrations is not correlated with these patients' marked susceptibility to skin cancer, suggests that some mechanism other than genetic transposition is causatively related to these XP patients' high incidence of sunlight-induced skin cancer.

YeastRAD14 and human xeroderma pigmentosum group A DNA-repair genes encode homologous proteins

Xeroderma pigmentosum (XP), a human autosomal recessive disorder, is characterized by extreme sensitivity to sunlight and high incidence of skin cancers. XP cells are defective in the incision step of excision repair of DNA damaged by ultraviolet light. Cell fusion studies have defined seven XP complementation groups, XP-A to XP-G. Similar genetic complexity of excision repair is observed in the yeast Saccharomyces cerevisiae. Mutations in any one of five yeast genes, RAD1, RAD2, RAD3, RAD4, and RAD10, cause a total defect in incision and an extreme sensitivity to ultraviolet light. Here we report the characterization of the yeast RAD14 gene. The available rad14 point mutant is only moderately ultraviolet-sensitive, and it performs a substantial amount of incision of damaged DNA. Our studies with the rad14 deletion (delta) mutation indicate an absolute requirement of RAD14 in incision. RAD14 encodes a highly hydrophilic protein of 247 amino acids containing zinc-finger motifs, and it is similar to the protein encoded by the human XPAC gene that complements XP group A cell lines.

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in mouse skin

Most chemicals that produce skin cancer are genotoxic by in vitro and in vivo short-term assays and produce a high incidence of skin cancer within a year if optimal doses are applied. If in long-term skin painting studies one or two tumours in 50 mice are observed there is a general consensus that no carcinogenic activity can be claimed and it has been suggested that if up to 10% tumours are induced by irritant substances this could be due to an enhancement of spontaneous tumuor incidence. Observations of skin tumour incidences higher than 10% with non-genotoxic substances, usually after a long latent period, is considered to represent evudebce for a non-genotoxic mechanism. Examples of such substances include croton oil, 12- O-tetradecanoyl-phorbol-13-acetate (TPA), sodium hydroxide, potassium hydroxide, phenol, dodecylbenzene and petroleum-derived middle distillates. Two distinct mechanisms appear to be involved in the production of tumours by a non-genotoxic substance. The first of these is that seen with the strong promoting agents. These, by binding to and activating protein kinase C, appear to directly stimulate sustained epidermal hyperplasia without severe skin damage. The other appears to involve substances producing severe skin damage either by a direct caustic effect or by cumulative irritancy. These changes give rise to marked epidermal hyperplasia with repeated episodes of regeneration and damage. The tumour induction by both mechanisms probably results from oncogene activation and it is possible that oxidative enzymes from inflammatory cells may be involved in the activation process. Various reasons are given why non-genotoxic carcinogenesis in the skin is considered not to be relevant to man and ways of recognising and avoiding its occurrence in animals studies are recommended.

Sunlight-induced cancer: some new aspects and implications of the xeroderma pigmentosum model

Symptoms of xeroderma pigmentosum, a hereditary disease characterized by accelerated light-induced ageing of the skin, are due to deficiencies in the repair of damaged DNA. Following UV irradiation a high incidence of thioguanine-resistant mutations have been observed, which may be a model for the abnormally high incidence of freckling and benign and malignant transformation observed in these patients. Cells from patients with Cockayne's syndrome and trichothiodystrophy have also been shown to be hypermutable by UV radiation with a similar DNA repair defect, but unlike xeroderma pigmentosum patients they do not experience a higher incidence of skin cancer or freckling. An immunological defect may be a further crucial factor determining the dermatological symptoms of xeroderma pigmentosum patients. Much can be learned about the way normal individuals function from a study of aberrant functioning of individuals with defined genetic deficiencies. In the field of senescence of the skin, the disease xeroderma pigmentosum (XP) has been of particular value, as the exposed skin of these sun-sensitive individuals shows at an early age many of the features of aged sun-exposed skin of normal individuals. These features of XP skin include hyperkeratosis, freckling, benign lesions and malignant tumours, including melanomas. A full discussion of this syndrome has been given by Kraemer et al.

The relationship of sun exposure and solar elastosis to skin cancer in a high risk population

The significance of chronic sun exposure in the pathogenesis of skin cancers squamous cell carcinoma (SCC). basal cell carcinoma (BCC) and melanoma was morphologically assessed. Histological sections of 223 consecutive skin cancers were reviewed, these were stained with aldehyde fuchsin and the degree of associated solar elastosis estimated. The anatomic distribution of SCC and BCC and the SCC:BCC ratio were significantly different in the Irish population studied when compared to other major series. It was found that a significant proportion of SCCs and BCCs were not related to chronic sun exposure. As expected, only melanomas arising in lentigo maligna were associated with long-term irradiation. It is proposed that other environmental agents and genetic factors may also contribute to the high incidence of skin cancer in Ireland.

Melanoma and Other Skin Cancers in Xeroderma Pigmentosum Patients and Mutation in Their Cells

Malignant melanomas were found in 15.8% of xeroderma pigmentosum (XP) patients with skin cancer in Japan. When multiple cancers were scored separately depending on the histopathologic types, 12.1% of the skin cancers in XP patients was malignant malignant melanoma. The relative incidence of malignant melanoma in skin cancer in XP patients is similar to that in skin cancer in general (12.6%), reported previously. Most of the malignant melanoma in XP patients developed in skin exposed to sunlight, in contrast to the high incidence of malignant melanoma in general in the unexposed skin of Japanese people. A DNA repair defect of UV damage is strongly suggested to be responsible for the high incidence of skin cancer in XP patients. The onset of malignant melanoma in XP patients was about ten years old, and was as early as those of basal cell carcinoma and squamous cell carcinoma in the patients with very low DNA repair capacities. Among nine genetic complementation groups and a variant type, group A XP cells were found to be extremely hypermutable by ultraviolet light, while group C XP cells were also hypermutable, but at the same level as normal cells when adjusted for survival. Mutagenesis as a possible mechanism of carcinogenesis in XP is supported by these results, but evidence in other cancer-prone hereditary diseases is yet to be obtained.

Sister Chromatid Exchange-Related Characteristics of Excision Repair-Proficient Xeroderma Pigmentosum Cells

A high incidence of skin cancer characterizes patients with xeroderma pigmentosum (XP). XP patients have hereditary defects in repair mechanisms of ultraviolet light (UV)-induced damage to DNA. Progress in elucidating the pathogenesis of cutaneous cancers can be expected by analysis of the biologic defects of cultured cells from XP patients. Such information may also contribute, at least in part, to an understanding of carcinogenesis in general.

Sister chromatid exchange-related characteristics of excision repair-proficient xeroderma pigmentosum cells.

A high incidence of skin cancer characterizes patients with xeroderma pigmentosum (XP). XP patients have hereditary defects in repair mechanisms of ultraviolet light (UV)-induced damage to DNA. Progress in elucidating the pathogenesis of cutaneous cancers can be expected by analysis of the biologic defects of cultured cells from XP patients. Such information may also contribute, at least in part, to an understanding of carcinogenesis in general.

Melanoma and other skin cancers in xeroderma pigmentosum patients and mutation in their cells.

Malignant melanomas were found in 15.8% of xeroderma pigmentosum (XP) patients with skin cancer in Japan. When multiple cancers were scored separately depending on the histopathologic types, 12.1% of the skin cancers in XP patients was malignant malignant melanoma. The relative incidence of malignant melanoma in skin cancer in XP patients is similar to that in skin cancer in general (12.6%), reported previously. Most of the malignant melanoma in XP patients developed in skin exposed to sunlight, in contrast to the high incidence of malignant melanoma in general in the unexposed skin of Japanese people. A DNA repair defect of UV damage is strongly suggested to be responsible for the high incidence of skin cancer in XP patients. The onset of malignant melanoma in XP patients was about ten years old, and was as early as those of basal cell carcinoma and squamous cell carcinoma in the patients with very low DNA repair capacities. Among nine genetic complementation groups and a variant type, group A XP cells were found to be extremely hypermutable by ultraviolet light, while group C XP cells were also hypermutable, but at the same level as normal cells when adjusted for survival. Mutagenesis as a possible mechanism of carcinogenesis in XP is supported by these results, but evidence in other cancer-prone hereditary diseases is yet to be obtained.

Photobiological activity of marmesin (5-B-hydroxyisopropyl-4-5 dihydrofurocoumarin) in Chinese hamster V79 cells.

Abstract— Marmesin was isolated from the medicinal plant, Afraegle paniculata. Its cytotoxicity and mutagenicity in Chinese hamster V79 cells when sensitized to near ultraviolet (NUV) and long wavelength ultraviolet light or black light (BL) were assayed.Marmesin was extremely cytotoxic in the dark. This cytotoxicity was photoenhanced in NUV and BL; the photoenhanced lethality being higher in NUV than in BL. The LD50 of marmesin under NUV and BL photosensitization were 0.002 μM and (0.012 μM), respectively. In the absence of NUV and BL, marmesin's LD50 was 0.013 μM. NUV and BL without marmesin were not significantly cytotoxic at the fluence rates of 0.29 W/m2 and 4.2 W/m2, respectively, for up to 20 min. In contrast to the observed high cytotoxicity of marmesin, its mutagenicity at the HGPRT locus (AzGr) was weak. The implication of this result in the high incidence of skin cancer in Nigeria in which A. paniculata is used as a medicinal plant is discussed.

Cutaneous manifestations in renal transplant recipients.

Out of 105 renal transplant recipients 100 had skin lesions: 55% iatrogenic, 74% infectious, 12% precancerous or cancerous and 4% miscellaneous. Many of these lesions were at least in part transient, and steroid-related skin lesions became less frequent as years progressed. The more frequent infections were the fungal ones, followed by viral and bacterial infections with different patterns of onset. All the precancerous lesions appeared late and were almost exclusively represented by actinic keratoses; 2 evolved into squamous cell epitheliomata. 2 patients died due to Kaposi's sarcoma and melanoma. The high incidence of skin cancers in transplanted patients and the rapid evolution of dyskeratoses into spinaliomas warrants close dermatological surveillance.

Xeroderma Pigmentosum

Xeroderma pigmentosum (XP) is a rare autosomal recessive disease (frequency, one to four per million) in which affected individuals exhibit sun sensitivity, cutaneous pigmentary abnormalities, and a high incidence of skin cancer.^1-4In addition, some patients with XP have neurologic abnormalities such as mental deterioration or sensorineural deafness. The disease is one of progressive and accelerated degeneration of the skin, eyes, and nervous system. Many of these symptoms may be manifestations of repeated environmental insults on a defective DNA repair system. The earliest cutaneous abnormalities in XP often include an exaggerated sunburn reaction¹and delayed erythema on phototesting.⁵Interestingly, some patients with XP tan without this acute photosensitivity reaction.¹However, before 2 years of age, virtually all patients with XP have marked freckling on sun-exposed areas. With continued sun exposure, a poikilodermatous appearance develops in the skin, showing areas of increased pigment, decreased pigment, marked atrophy,

Inhibition of carcinogen formation in skin irradiated with ultraviolet light.

THERE is no doubt that sunlight and ultraviolet light cause certain types of skin cancer1,2. Unna first called attention to the high incidence of skin cancer among sailors exposed to sunlight, and his observation on the relationship between the development of skin cancers and exposure to sunlight has been confirmed by many others.

Effect of chloroquine on erythematous and carcinogenic response to ultraviolet light. Demonstrated in experimental animals.

During a lifetime, exposed areas of the body are subject to large amounts of irradiation from sunlight. Unna was the first to call attention to the high incidence of skin cancer among sailors exposed to sunlight,¹and his observation on the relationship between exposure to sunlight and the development of skin cancers has been confirmed by many others. Also, epitheliomas have been produced experimentally by subjecting albino mice, rats, and rabbits to repeated exposures to ultraviolet rays produced by a mercury arc lamp.^2-5The carcinogenic wave lengths of the spectrum have been determined to be between 2,900 and 3,341 A. In experimental animals, the amount of effective midultraviolet radiant energy necessary to initiate changes which culminate with tumor formation is relatively small (63 to 84×107 ergs/sq. cm.).⁵To a certain extent, the length of the precancerous period varies inversely with the daily dose of irradiation. Carcinogenesis, once

Skin cancer in the engineering industry from the use of mineral oil.

Although the aetiological association between soot and cancer of the scrotum was recognized by Percival Pott as early as 1775, the role of mineral oils in the production of skin cancer was not recognized until considerably later. Joseph Bell of the Edinburgh Royal Infirmary reported a case of carcinoma of the scrotum in a Scottish shale oil worker in 1876. Southam and Wilson (1922) pointed out the high incidence of scrotal cancer in Lancashire cotton mule spinners and, although various theories of causation were advanced, the production of tumours in mice by the cutaneous application of lubricating oil by Leitch (1924) indicated that some constituent of the spindle oil was the carcinogen. The carcinogenicity of a large number of petroleum oils was investigated by Twort and Twort (1931) who showed that many were carcinogenic. The high incidence of skin cancer in Scottish shale oil workers was described by Scott (1922). Experimental tumours were produced in mice by applying shale oil to the skin (Leitch, 1922), and finally Berenblum and Schoental (1943), by using the Chromatographie method of separation, isolated 3-4 benzpyrene from this oil and showed that there were other carcinogens present. The carcinogenic agents in petroleum oils, however, probably differ qualitatively and quantitatively from those in shale oils which are produced by destructive distillation. So far no pure carcinogens have been isolated from petroleum oils. In 1920, it was made obligatory to notify occupa tional skin cancer due to paraffin or mineral oil or any of their compounds, residues or products, contracted in a factory or workshop. These notifi cations have been invaluable for finding out the extent to which the disease occurs, and in con junction with the examination of death certificates, have furnished the basis of the extensive researches of S. A. Henry (1946; 1947). This work has empha sized the high incidence of skin cancer in cotton operatives, but in the engineering industry relatively few cases have been observed. For example, in the period 1911-38, only 71 metal workers (including precious metals) died with scrotal cancer out of a total of 715 such deaths recorded among workers exposed to mineral oil, the bulk of the cases having occurred in the cotton industry. The incidence in the engineering industry appears even lower when notifications instead of deaths are considered, but, as is generally recognized, notifications are unreliable until a definite hazard is widely appreciated. Our studies indicate that the hazard of skin cancer is to

RESEARCH ITEMS

Production of Cancer by Ultra–violet IrradiationTHIS topic was discussed by H. P. Rusch and B. E. Kline at the Autumn Meeting of the U.S. National Academy of Sciences held during October 13–5. The idea that sunlight is an important causal agent in cancer of the skin is not new. The high incidence of skin cancer in sailors has long been known, and nearly fifty years ago ‘seaman's skin’ was described as a precancerous condition attributable to continued exposure to light. However, only in the last decade has experimental support been formed for the theory of direct causation of cancer by sunlight. The authors have determined the wave-lengths of the spectrum responsible for cancer production and measured the amount of energy required for the process. White mice were used in these studies. The wave–lengths o responsible were found to lie between 2,900 A. and 3,341 A. The minimum time for the development of tumours was about two and a half months, and it was not necessary to irradiate the animals throughout the precancerous period. Once initiated, carcinogenesis proceeded without further exposure, and sometimes several months elapsed between the end of irradiation and the appearance of tumours. Very little radiant energy was needed to initiate those changes which culminate in tumour formation. The tumours produced were true malignant cancers of the same type found in humans.