Human papillomavirus infections in nonmelanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients.

BACKGROUND: Nonmelanoma carcinomas of the skin represent the most frequent cancers among the Caucasian population worldwide. They occur with high frequency in renal allograft recipient patients after prolonged immunosuppression. PURPOSE: We analyzed tumors obtained from both immunosuppressed and nonimmunosuppressed patients for human papillomavirus (HPV) DNA. METHODS: Twenty-nine specimens of nonmelanoma carcinomas of the skin were obtained from 19 renal allograft recipient patients; these included 20 specimens of squamous cell carcinoma (SCC) from 11 patients, five specimens of basal cell carcinoma (BCC) from four patients, and four specimens of carcinoma in situ (CIS) from four patients. Forty-one specimens of nonmelanoma carcinomas of the skin were obtained from 32 nonimmunosuppressed patients; these included 26 SCC specimens from 19 patients, 11 BCC specimens from nine patients, and four keratoacanthoma (benign epithelial tumor) specimens from four patients. A polymerase chain reaction method involving use of degenerate oligonucleotide primers, in which the conserved region of the open reading frame of the HPV L1 (major capsid protein) gene is amplified, was used to amplify total cellular DNA purified from individual tumors. The DNA of each specimen was subjected to 16 different amplification reactions; different primer combinations were used in order to increase the sensitivity and specificity of HPV detection. Resulting products were probed with a radioactively labeled, degenerate oligonucleotide. HPV-specific DNA was either sequenced directly after elution from the gel or amplified with semi-nested, degenerate primers, after which the products were cloned and sequenced. Sequences were compared with all known papillomavirus sequences. RESULTS: Thirteen (65%) of the 20 SCC specimens and three of the five BCC specimens from immunosuppressed (renal allograft recipient) patients contained identifiable HPV-related sequences, among them 13 putative novel HPV genomes. In addition, all other malignant tumor specimens from this patient group revealed faint signals upon amplification and hybridization; the origin of these signals has not been identified in the present study. In nonimmunosuppressed patients, eight (31%) of 26 SCC specimens and four (36%) of 11 BCC specimens contained sequences of HPV types. Two putative novel HPV sequences could be identified in this group. Faint signals of yet undetermined origin were observed in eight of the SCC specimens and in two of the BCC specimens. Two of four keratoacanthoma specimens contained sequences of known HPV type. (Keratoacanthoma is a nonmalignant lesion for which the natural history has not been defined.) The spectrum of HPV types in both groups of patients differed substantially. CONCLUSIONS: These data point to the frequent presence of HPV sequences in SCCs and BCCs of the skin. The etiologic relationship of these infections to the respective malignant tumors remains to be evaluated. IMPLICATIONS: The presence of HPV DNA in a large percentage of specimens of nonmelanoma carcinomas of the skin from immunosuppressed patients, as well as from nonimmmunosuppressed patients, renders a papillomavirus infection as a possible factor in the etiology of this disease.

Clinical symptoms and DNA repair characteristics of xeroderma pigmentosum patients from Germany.

Sixty-one xeroderma pigmentosum (XP) patients living in the Federal Republic of Germany were investigated. Clinical symptoms were correlated with DNA repair parameters measured in fibroblasts grown from skin biopsies. Classification according to the international complementation groups revealed that of the 61 patients 3 belonged to group A, 26 to group C, 16 to group D, 3 to group E, and 2 to group F; 11 were of the XP variant type. A striking clinical aspect was the frequency of histogenetically different skin tumors varying from one XP complementation group to the other: squamous and basal cell carcinomas predominated in XP group C; lentigo maligna melanomas were most frequent in group D; basal cell carcinomas occurred preferentially in group E and XP variants. Three DNA repair parameters were determined for 46 fibroblast strains: colony-forming ability (D0); DNA repair synthesis (G0); and DNA-incising capacity (E0). Dose-response experiments with up to 13 dose levels were performed throughout to achieve sufficient experimental accuracy. DNA-damaging treatments included UV light, the "UV-like" carcinogen N-acetoxy-2-acetylaminofluorene, and the alkylating carcinogens methyl methanesulfonate and N-methyl-N-nitrosourea. Comparison of clinical signs and repair data was made on the basis of D0, G0, and E0 values of both individual cell strains and weighted means of XP complementation groups. Despite considerable clinical and biochemical heterogeneity within complementation groups distinctive features emerged. In general, D0, G0, and E0 values of all XP strains investigated, including XP variants, were found to be reduced upon treatment with UV light or N-acetoxy-2-acetylaminofluorene. After treatment with UV light or N-acetoxy-2-acetylaminofluorene, cell strains in which DNA-incising capacity was reduced also showed a similar reduction in both colony-forming ability and DNA repair synthesis. Consequently, the weighted mean D0, G0, and E0 values of XP complementation groups and XP variants correlated with each other. Furthermore, the onset of both early dermatological symptoms of XP and tumor growth correlated with the extent of DNA repair defects. Of 45 XP fibroblast strains checked for colony-forming ability after treatment with methyl methanesulfonate only 3 cell strains from group D were found to be more sensitive than normal controls, suggesting that overall repair in XP strains was equal to that in controls. Weighted means of DNA repair synthesis of XP complementation groups, however, showed reductions hinting at impaired excision of distinct alkylated bases.(ABSTRACT TRUNCATED AT 400 WORDS)

Evidence that DNA damage is a mediate in ultraviolet B radiation-induced inhibition of human gene expression: ultraviolet B radiation effects on intercellular adhesion molecule-1 (ICAM-1) expression.

Expression of intercellular adhesion molecule-1 (ICAM-1) is a prerequisite for the capacity of cells to physically interact with leukocytes. Ultraviolet B radiation previously was found to inhibit interferon gamma-induced ICAM-1 expression in human keratinocytes by suppressing interferon gamma-mediated upregulation of ICAM-1 mRNA levels. Because ultraviolet B radiation induces photoproducts in cellular DNA, the potential role of ultraviolet B radiation-induced DNA damage in this system was assessed. For this purpose, cells from a normal donor were compared with cells from patients with xeroderma pigmentosum from complementation groups C and D. Xeroderma pigmentosum cells are defective in the removal of ultraviolet B radiation-induced DNA lesions, and thus lower ultraviolet B radiation doses are required to retain equivalent numbers of DNA photoproducts at a given time point after irradiation. In the present study, ultraviolet B radiation inhibited interferon gamma-induced ICAM-1 mRNA expression in primary human skin fibroblasts in a manner identical to that previously observed for keratinocytes. Comparative studies employing normal versus xeroderma pigmentosum fibroblasts revealed that in xeroderma pigmentosum fibroblasts, two- to threefold lower ultraviolet B radiation doses were required to achieve inhibition equivalent to that observed in normal fibroblasts. In irradiated normal cells, inhibition of interferon gamma-induced ICAM-1 mRNA expression was transient and restored 12 h after ultraviolet B radiation exposure. In contrast, in xeroderma pigmentosum complementation group D cells, no restoration could be observed for up to 48 h, but responsiveness was restored in xeroderma pigmentosum complementation group C cells after 24 h. These studies indicate that ultraviolet B radiation-induced inhibition of interferon gamma-mediated ICAM-1 expression involves the generation of DNA photo-products.

Phototoxic erythema following PUVA treatment: independence of complement.

The effect of PUVA treatment on normal human serum (NHS), on isolated PMN, or on C3-deficient guinea pigs and congenic (C3-competent) control animals was tested. At a concentration of 0.1 or 1 mM/l 8-MOP and UVA doses of 5-30 J/cm2, PUVA failed to induce any detectable C3-cleavage in NHS. Furthermore, when the complement (C) activation in NHS had been induced before or after PUVA treatment by various methods. PUVA did not modulate the extent of C3-cleavage. PUVA did not affect the viability of isolated PMN, nor did it induce a release of LDH or elastase. No differences between C3-deficient and C-competent guinea pig skin exposed to PUVA were observed in erythema or histologic responses. Immunohistologic examination of specimens from normal guinea pigs revealed C3b and C3d deposits on necrotic keratinocytes, findings restricted to the PUVA-treated areas. Necrosis of keratinocytes was present in skin specimens of C3-deficient animals from PUVA-treated sites to a similar extent. However, deposits of C3-related antigens were completely absent there. From these observations, we suggest that the induction of phototoxic erythema following PUVA treatment is independent of complement.

Fibroblasts derived from patients with dysplastic nevus syndrome are not more sensitive towards 254-nm and 312-nm ultraviolet light than fibroblasts from normal donors.

DNA repair capacity of 18 fibroblast strains from patients with dysplastic nevus syndrome, 5 of them with malignant melanoma, was investigated and their colony-forming ability (D0) after UV exposure was determined as a measurement of this. Seventeen fibroblast strains from normal donors served as controls. The dose/response experiments included up to 11 dose levels and two UV wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial "sunlamp" radiation centering around 312-nm light). The exponential segments of the dose/response curves were analysed by linear regression and the negative reciprocals of the regression coefficients, D0, were calculated for each cell strain and each wavelength range. When comparing D0 values of individual cell strains from patients with and without melanomas with the mean value for all normal donors, only 4 out of 18 showed increased sensitivity towards UV-B. This difference, however, was not statistically significant. On the contrary, weighted-mean D0 values for fibroblast strains from patients with and without melanoma were found to be slightly but significantly higher than those for normal donors (significance level: 5%), indicating that cell strains from these patients were less sensitive to UV light (UV-C and UV-B) of both wavelength. This result, which on the basis of current literature data is somewhat unexpected, holds true within the limits of experimental accuracy of +/- 12%.

DNA repair synthesis in fibroblast strains from patients with actinic keratosis, squamous cell carcinoma, basal cell carcinoma, or malignant melanoma after treatment with ultraviolet light, N-acetoxy-2-acetyl-aminofluorene, methyl methanesulfonate, and N-methyl-N-nitrosourea.

Fibroblast strains derived from skin biopsies of patients with actinic keratosis (6), malignant melanoma (18), squamous cell carcinoma (11), and basal cell carcinoma (12) were investigated for DNA repair synthesis, with 16 fibroblast strains for normal donors as controls. Cells were exposed to UV light, the "UV-like" carcinogen (Ac)2ONFln, and the methylating carcinogens MeSO2OMe and MeNOUr. Dose-response experiments, which included 10 dose levels, were performed, the data analyzed by linear regression, and the slope of the regression line (term: G0) used as a measure of DNA repair synthesis. The mean experimental variability of G0 of individual fibroblast strains was 9.5%-15.4%, depending upon exposure. For comparison of all cell strains belonging to the same skin malignancy group with those of the control group, G0 values of the individual strains were combined to yield group-specific weighted mean G0 values. In addition, the capacity to incise UV-damaged DNA was measured in 24 cell strains from patients with skin tumors using the alkaline elution technique. For quantitating DNA-incising capacity, the initial velocities of the elution curves were plotted versus the UV dose, and the slope of the resulting regression line was used to obtain the characteristic value E0. The mean experimental variability of E0 of individual strains was +/- 22%. These E0 values were combined to yield weighted mean values of groups. The fibroblast strains in the groups of patients with actinic keratosis and malignant melanoma were found to have normal mean G0 values when DNA repair synthesis was challenged with UV light or one of the three carcinogens. However, the squamous cell carcinoma group exhibited significantly lower mean G0 values after treatment with UV light (82% that of normal donors), (Ac)2ONFln (70%), MeSO2OMe (70%), and MeNOUr (69%). The basal cell carcinoma group showed significantly diminished repair synthesis upon treatment with UV light (81% that of normal donors) and MeSO2OMe (67%). In contrast to these findings, in no skin malignancy group was post UV DNA-incising capacity (E0) significantly diminished, although it should be noted that group sizes were only half as large as for G0 determinations. These data may be interpreted as indicating that DNA excision repair is impaired in fibroblast strains from patients with squamous cell carcinoma and-to a lesser extent-basal cell carcinoma.(ABSTRACT TRUNCATED AT 400 WORDS)

DNA repair synthesis following irradiation with 254-nm and 312-nm ultraviolet light is not diminished in fibroblasts from patients with dysplastic nevus syndrome.

The DNA excision repair capacity of 23 primary fibroblast lines from patients with dysplastic nevus syndrome was investigated and DNA repair synthesis ("unscheduled DNA synthesis") was determined after UV exposure. Seventeen fibroblast lines from normal donors served as controls. The dose/response experiments included up to ten dose levels and two wavelength ranges: UV-C (using a low-pressure mercury lamp emitting predominantly 254-nm light) and UV-B (artificial "sunlamp" radiation centering around 312-nm light). For each dose level, silver grains over fibroblast nuclei were counted by visual inspection. Twelve cell lines were also evaluated for both UV wavelength ranges using a new semi-automatic image analyzing system. This system included components for rapid sequential identification of both fibroblast nuclei and silver grains sited above them. Silver grains over 100 nuclei were determined for each UV dose level. Dose/response curves were established and analyzed by linear regression. As a quantitative term for assessing DNA excision repair capacity of a cell line we calculated the linear increase (G0) in the number of grains per nucleus, when the UV dose was multiplied by the factor e (i.e. 2.72). The sensitivity of grain detection and resolution of overlapping grains was approximately threefold better in visual than in automatic counting, especially when there were more than 70 grains over nuclei. The time required for visual counting, however, was tenfold that of automatic counting. The variance-weighted mean G0v.w of all fibroblast lines from patients with dysplastic nevus syndrome was found to be 79.1 (+/- 1.8- grains/nucleus, that of fibroblast lines from normal donors was 74.2 (+/- 1.7) grains/nucleus. This difference revealed a slightly better repair capability for cell lines from patients but was at the borderline of detection and, therefore, should not be overinterpreted. From the experimental accuracy achieved by determination of the variance-weighted means of the two groups, we would have been able to detect a difference of 7 and more grains [> 2 x (sigma normal+sigma patients)]. The variance-weighted mean G0v.w of all fibroblast lines from patients with dysplastic nevus syndrome was found to be 76.4 (+/- 1.4) grains/nucleus, whereas that of fibroblast lines from normal donors was only 66.6 (+/- 1.8) grains/nucleus. This difference was statistically significant and, contrary to expectation, revealed better, not worse post-UV DNA repair capability in cell lines from patients that in those from normal donors.(ABSTRACT TRUNCATED AT 400 WORDS)

Mutation and expression of TP53 in malignant melanomas.

Mutations of the TP53 gene are the most common genetic alterations in human malignancies. Overexpression of the p53 protein has been reported in high frequencies in all types of skin cancer. To determine the role of TP53 in the pathogenesis of malignant melanoma, we investigated the expression of p53 in 12 cell lines and 145 primary and metastatic lesions by immunohistochemistry. Overexpression of p53 was predominantly detected in the cytoplasm of the cells in 96 (66%) tumor and 12 (93%) cell lines. In contrast to findings in other tumor types, in melanomas immunoreactive cells were found in clusters or as scattered single cells. In primary melanomas, the frequency of p53 overexpression did not correlate with tumor thickness. Nucleotide sequencing of TP53 genes of 24 melanoma tumors/cell lines demonstrated point mutations in seven samples, all coding for mutant p53 protein species. The frequency of TP53 alterations of 20%-30% is lower than in other skin tumor types. Notably, immunohistochemistry was not a suitable method to distinguish overexpression of wild-type p53 from mutant species, since cell lines/tumors with TP53 mutations did not show distinctive staining patterns. The mutation pattern in six out of seven lesions was similar to that caused by ultraviolet light damage. This finding may be regarded a further indication for a pathogenetic role of UV light damage in at least a subgroup of malignant melanomas.

Arsenic elevates the sister chromatid exchange (SCE) rate in human lymphocytes in vitro.

The number of sister chromatid exchanges (SCE) per metaphase was determined in normal human lymphocytes by the Hoechst-Giesmsa procedure. The addition of inorganic trivalent arsenic (Na2HAsO4) 10(-6) M and 2 x 10(-6) M induces a significant and dose-dependent increase of SCE. This phenomenon is as sensitive as the evidence of arsenic-induced chromosomal aberrations in vitro.

Distribution of Merkel cells in acute UVB erythema.

Merkel cells (MC) were identified immunohistochemically using antibodies specific for cytokeratin (CK) 20 within human epidermis 12 to 72 h after exposure to UVB (4 MED). 12 h after exposure all MC were normally localized within the epidermal basal layer. However, 24 h after exposure 4% of the MC were detected suprabasally, the remaining 96% still being situated in the basal layer. Surprisingly, at 48 h and 72 h more than 50% had lost contact with the basal membrane. The MC of hair follicles did not show any obvious changes. These results argue, in the context of acute epidermal UV damage, for an abnormal turnover in dermatitis.

Sister chromatid exchange (SCE) in human lymphocytes. Effect of UV C irradiation and age.

The number of sister chromatid exchanges (SCE) per metaphase was determined in normal human lymphocytes by the Hoechst-Giemsa procedure. UV C irradiation promotes SCE dose-dependent in the range of 0-40 mJ/cm2. No difference of this phenomenon may be observed, compairing young volunteers (20-40 years) with a 60-80-year-old group.

Presence of Merkel cells in sun-exposed and not sun-exposed skin: a quantitative study.

Merkel cells (MCs), the neuroendocrine cells of the skin cannot be identified with certainty using conventional light microscopic staining methods. Using immunoperoxidase microscopy with antibodies specific for cytokeratin 18, which has been established as a marker protein of MCs, we have evaluated the numbers of MCs per mm2 skin in normal and sun-damaged upper arm skin. The sun-exposed skin contained twice as many MCs as the not sun exposed skin. Further quantification of MC density at various body sites (trunk, leg) showed a rather variable but often unexpectedly high MC density. The possible role of MC in development of actinic elastosis is discussed.

Clinicopathological and prognostic relevance of Rap1-GAP expression in melanocytic tumors.

Rap1-GAP protein has been identified as an inactivator of Rap1 activity, a putative endogenous antagonist of Ras proteins. The Rap1-GA1 locus maps to 1p36.1-35, the region which may harbor a gene for familial melanoma. In the present immunohistochemical study we analyzed the clinicopathological and prognostic relevance of Rap1-GAP expression in 60 benign and 103 malignant melanocytic tumors. Cytoplasmic immunoreactivity was detected in the cells of 27/60 nevi (45%) and 59/103 melanomas (57%). In the latter group the frequency of Rap1-GAP expression increased (P < 0.05) with the thickness of primary tumors and was highest in metastatic lesions. Rap1-GAP protein was detected in 15/19 subsequently recurring primary melanomas (79%) but only in 32/67 tumors (47%) of patients who remained free of disease (P < 0.05) for at least 6 years. Five out of six recurring thin melanomas (< 2 mm) were found to be immunoreactive. Although being no indicator for malignant transformation of melanocytic lesions, Rap1-GAP overexpression may represent a useful marker for identifying thin high-risk melanomas. Cytoplasmic expression of Rap1-GAP has also been observed in the cells of skin appendages and in keratinocytes, particularly in suprabasal layers of the epidermis. Therefore, Rap1-GAP is likely to be associated with cellular growth and/or differentiation. However, the present study did not provide evidence that this gene, despite its chromosomal localization, represents an early melanoma gene.

Light-induced skin cancer and prolonged uv-erythema.

The individual minimal erythema dose (MED) and the persistence of a marked erythema (8 MED) was monitored over 3 weeks (300 nm +/- 10 nm) in 4 groups: White students with fair complexion compared with students of homogenous pigmentation as well as skin carcinoma patients compared with a control group of the same age, i.e., older than 50 years. The MED of the 4 groups gives no significant differences, while the skin carcinoma group shows in 80% a prolonged erythema persistence (control group only 28%). This phenomenon does not seem to correlate with the skin type and may be useful in identifying high-risk patients prone to light-induced skin cancer.

Risk factors of the cutaneous melanoma phenotype.

Of 20 melanoma patients 85% show a prolonged erythema persistence after a marked test erythema of 8 MED with 300 nm +/- 10 nm (control group only 34%). This phenomenon does not correlate with the skin type and is useful in identifying high-risk patients prone to melanoma and light-induced skin cancer (92%). The spontaneous and the UV-C-induced number of sister chromatid exchanges (SCE) per metaphase was significantly higher in peripheral leukocytes of melanoma patients than in normal controls. The attempt was made to establish a "risk-spectrum" of cutaneous melanoma phenotype.

Xeroderma pigmentosum patients from Germany: clinical symptoms and DNA repair characteristics.

Dermatologic, ophthalmologic, and neurologic examinations were carried out on 33 patients with clinical symptoms of xeroderma pigmentosum (XP). Complementation groups were determined for 23 patients. Types of tumors and complementation group were found to be related in the following way: In the XP variant groups basaliomas were the most frequently occurring malignant tumors, whereas in the D group pigmentary tumors, such as melanotic precanceroses and melanomas prevailed; in the A and the C group, spinaliomas seem to be the most frequent malignomas. The DNA repair activity was measured using colony-forming ability and unscheduled DNA synthesis. Colony-forming ability was quantitated as a function of 12 different UV doses and expressed in terms of D0. Unscheduled DNA synthesis was determined autoradiographically by establishing dose-response curves, which were analyzed by the characteristic value of linear regression. G0, defined as the linear increase in the mean number of silver grains per nucleus when the UV dose is multiplied by the factor of e (i.e., 2.72), was derived from the slopes of the regression lines. The repair capability of XP fibroblast lines was classified on the basis of D0 and G0.

A ninth complementation group in xeroderma pigmentosum, XP I.

A new complementation group of excision-deficient xeroderma pigmentosum (XP) is described in 2 patients living in the F.R.G. Dermatological, ophthalmological and neurological symptoms of XP are presented together with DNA repair characteristics such as unscheduled DNA synthesis, colony-forming ability and alkaline elution studied in cultured fibroblasts. The results are compared to normal controls.

Interferential current is effective in palmar psoriaris: an open prospective trial.

Interferential current (IFC) has been shown to improve psoriasis in a small case series. So far no formal clinical trial had been conducted. As IFC is associated with slight prickling sensations a blinded study design was not feasible. Therefore, an open type prospective study was conducted with the assumption of 18% spontaneous remission rate. A response rate of 50% or less was judged as indicating no effect (hypothetical control), while 80% or more was considered as success (alternative hypothesis). In this "quasi-controlled" study 12 patients with therapy resistant palmar psoriasis received local treatment with IFC during a 12 week period. Treatment was performed at low current density in two daily sessions, each of 6 minutes duration. Erythema, scaling, induration, fissures and pustules were recorded in separate scores every 4 weeks. Response of a patient was judged positive when the total score of these criteria was reduced at least by two points at the end of treatment. After 12 weeks of treatment, 11 of 12 patients were cured or showed marked remission with the median overall score reduced by 4 points. An interim analysis was performed in order to decide whether the results had already reached significance (a < 0.05). The analysis revealed a statistically significant response rate of 90% (95% confidence interval 62-99%). These results are highly encouraging and should focus attention on this new therapy modality, which, in contrast to other treatments is not associated with side effects and discomfort.

Heat shock protein HSP 27 is expressed in all types of basal cell carcinoma in low and high risk UV exposure groups.

HSP 27, a marker of differentiation and proliferation, helps the cell in repair processes after environmental stress such as heat, UV-irradiation and oxidative stress. So far, its role on carcinogenesis is not yet understood. HSP 27 was studied immunohistochemically in different types of primary, untreated basal cell carcinoma (BCC) in two populations with different UV exposure habits: descendents from Germany, "Pommern", living in Brazil (Pommeranos, n = 15), rural workers with high UV exposure and Germans from the region Baden-Württemberg with indoor jobs (n = 14). Age distribution and type of BCC were similar between the Pommeranos and the Germans. Specimens of BCC (n = 15 solid, n = 6 keratotic, n = 4 adenoid, n = 4 fibrotic) were evaluated in cryostat and paraffin sections for HSP 27, HSP 72 and bcl-2. In Pommeranos in Brazil (UV high risk group) versus (vs) inhabitants from Baden-Württemberg (UV low risk group), HSP 27 was expressed in 93% vs 79% in all histological subclasses, HSP 72 in 20% vs 21% and bcl-2 in 93 % in both groups. Antibodies against HSP 27, but not HSP 72, labeled BCC of all types. In contrast to the lack of HSP 27 in squamous cell carcinoma reported in the literature, we found HSP 27 and bcl-2 positive cells in BCC which might characterize the tumour as relatively benign and slow progressing.

Xeroderma pigmentosum: heterogeneous syndrome and model for UV carcinogenesis.

Xeroderma pigmentosum (XP) is a rare inherited, heterogeneous syndrome with pigment anomalies, sun sensitivity, multiple cutaneous neoplasms and abnormal self protecting systems (SPS). The transmittence is autosomal-recessive. 50 percent of XP patients gets melanoma and 15 percent have neurological abnormalities. Clinical differentiation, determination of the DNA repair rate and cell fusion studies allow the differentiation of 6 complementation groups including De Sanctis-Cacchione syndrome and the XP variant typ. Pigmented Xerodermoid is a special form. Cytogenetic studies give evidences for the model character of XP for UV carcinogenesis.