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F R de Gruijl

Publications and source records attributed to F R de Gruijl.

At least 19 recordsLinked to original sources
PubMed2006

[Retarded excision of pyrimidine dimers in human unstimulated lymphocytes].

Using immuno-labelling of cyclobutane pyrimidine dimers (CPDs) in nuclei of peripheral lymphocytes after their UVC-irradiation and cultivation, we have found that within the first four hours of cultivation the CPD-specific fluorescent signal from cell nuclei increased. Earlier, a similar increase in binding of antibody specific for pyrimidine (6-4) pyrimidone photoproducts to undenatured DNA isolated from UV-irradiated Chinese hamster ovary cells was reported (Mitchell et al., 1986). Our experiments showed that nucleotide excision repair enzyme might induce such of DNA modification in lymphocyte nuclei that increased specific antibody binding to DNA fragments with lesions. We suggest that enzymatic formation of open structures in DNA predominated qualitatively over dual-incision and excision of these fragments, and resulted in the enhanced exposure of the pyrimidine dimers in nuclei to specific antibodies. The results evidence that nucleotid excision repair in unstimualted human lymphocytes being deficient in dual incision and removal of UV-induced DNA lesions appear to be capable of performing chromatin relaxation and pre-incision uncoiling of DNA fragments with lesions.

Cell Nucleus↗
PubMed2005

Predictions of skin cancer incidence in the Netherlands up to 2015.

BACKGROUND: Skin cancer is an important, growing public health problem among white caucasians, causing a heavy burden on dermatologists and general practitioners. OBJECTIVES: To predict the future incidence of skin cancer in the Netherlands up to 2015. METHODS: Expected numbers of skin cancer cases in the Netherlands up to 2015 were calculated by trend modelling of observed rates for melanoma and squamous cell carcinoma (SCC) between 1989 and 2000 obtained from the Netherlands Cancer Registry and for basal cell carcinoma (BCC) obtained from the Eindhoven Cancer Registry; these rates were then multiplied by the predicted age distributions. Incidence rates were fitted to four different models, and predictions were based on the best fitting model. RESULTS: An increase of 80% in the total number of skin cancer patients is expected in the Netherlands: from 20 654 in 2000 to 37 342 in 2015. The total number of melanoma cases is expected to increase by 99%, with the largest increase for males (males aged 35-64, 111%; males aged > or = 65, 139%). Numbers of patients with SCC will increase overall by 80%, mainly among older males and females (increase of 79%) and females aged 35-64 (increase of 93%). The number of cases of BCC will increase by 78%, with the largest increase for the combined groups, those aged 15-64 (males, 66% increase; females, 94% increase), especially for sites other than the head and neck. The contribution of demographic changes (ageing effect) was largest for males with BCC and SCC (35-44%). CONCLUSIONS: If incidence rates for skin cancers in the Netherlands continue to increase and population growth and ageing remain unabated, a rise in annual demand for care of more than 5% could occur, putting a heavy burden on general practitioners and dermatologists. In the absence of marked changes in current ultraviolet radiation exposure, these increases will probably continue after 2015.

Adolescent↗
PubMed2005

Normalized ultraviolet (UV) induction of Langerhans cell depletion and neutrophil infiltrates after artificial UVB hardening of patients with polymorphic light eruption.

BACKGROUND: Ultraviolet (UV) B hardening has been widely used as a prophylactic treatment in patients with polymorphic light eruption (PLE). Recent investigations have shown that in patients with PLE Langerhans cells (LCs) and neutrophils display less migration from and to the epidermis after an intense UVB irradiation compared with controls. OBJECTIVES: To investigate the effect of UVB hardening of patients with PLE on their cell migratory responses after intense UVB exposure. METHODS: Thirteen patients with PLE were recruited and UVB provocation testing was performed before entering the study. Among these patients, seven developed PLE rash upon UVB provocation ('UVB-P') and the other six did not respond ('UVB-NP'). Eleven age/sex-matched controls were included. Buttock skin of all included individuals was exposed to 6 minimal erythema doses (MED) of UVB (TL-12 lamps). Biopsies were taken after 24 h and 48 h, together with one control biopsy of unirradiated skin. Patients received total-body UVB hardening therapy consisting of 12 irradiations, on average rising from 10% to 140% of the initial MED in 6 weeks. Subsequently, MEDs were reassessed and biopsies were taken from newly irradiated (6 MED UVB) and unirradiated buttock skin. Skin sections were stained for the presence of LCs, macrophages and neutrophils. The cross-sectional area (in percentage) of positively stained cells within the epidermis was assessed from patients before and after hardening and compared with controls. RESULTS: Before therapy, epidermal LC depletion and neutrophil influx at 48 h after 6 MED were most significantly reduced in 'UVB-P' patients (P = 0.025 and P =0.006, respectively) when compared with controls. 'UVB-NP' patients did not differ significantly from controls. After therapy, there were no longer any significant differences in the cell numbers among these three groups. CONCLUSIONS: UVB hardening significantly improves UV-induced cell migratory responses in patients with PLE. UVB provokability of PLE appears to be most strongly linked to reduced UVB-induced trafficking of LCs and neutrophils, and 'UVB-P' patients show normalization of these responses after UVB hardening.

Adult↗
PubMed2004

INK4a-ARF mutations in skin carcinomas from UV irradiated hairless mice.

To characterize further the role of the INK4a-ARF locus in the multistep process of skin carcinogenesis, we performed a mutational analysis of this locus in skin lesions from hairless mice either irradiated with UVB alone or with a solar simulator delivering UVA + B. INK4a-ARF mutations were present in five of 57 squamous cell carcinomas (9%), but no mutation was detected in precancerous lesions. All mutations were C:G > T:A transitions located at dipyrimidic sites, the hallmark of UVB mutagenesis. Three mutations affected only the p19(ARF) reading frame, whereas two mutations affected only the p16(INK4a) transcript. This study demonstrates for the first time UV-induced mutations of INK4a-ARF that occur in a small percentage in late stages skin tumors.

Animals↗
PubMed2001

Early p53-positive foci as indicators of tumor risk in ultraviolet-exposed hairless mice: kinetics of induction, effects of DNA repair deficiency, and p53 heterozygosity.

p53 mutations appear to be early events in skin carcinogenesis induced by chronic UVB irradiation. Clusters of epidermal cells that express p53 in mutant conformation ("p53 positive foci") are easily detected by immunohistochemical staining long before the appearance of skin carcinomas or their precursor lesions. In a hairless mouse model, we determined the dose-time dependency of the induction of these p53+ foci and investigated the relationship with the induction of skin carcinomas. The density of p53+ foci may be a good direct indicator of tumor risk. Hairless SKH1 mice were exposed to either of two regimens of daily UVB (500 or 250 J/m2 broadband UV from Philips TL12 lamps; 54% UVB 280-315 nm). With the high-dose regimen, the average number of p53+ foci in a dorsal skin area (7.2 cm2) increased rapidly from 9.0 +/- 2.1 (SE) at 15 days to 470 +/- 80 (SE) at 40 days. At half that daily dose, the induction of p53+ foci was slower by a factor of 1.49 +/- 0.15, very similar to a previously observed slower induction of squamous cell carcinomas by a factor of 1.54 +/- 0.02. In a double-log plot of the average number of p53 + foci versus time, the curves for the two exposure regimens ran parallel (slope, 3.7 +/- 0.7), similar to the curves for the number of tumors versus time (slope, 6.9 +/- 0.8). The difference in slopes (3.7 versus 6.9) is in line with the contention that more rate-limiting steps are needed to develop a tumor than a p53+ focus. By the time the first tumors appear (around 7-8 weeks with the high daily dose), the dorsal skin contains >100 p53+ foci/cm2. To further validate the density of p53+ foci as a direct measure of tumor risk, we carried out experiments with transgenic mice with an enhanced susceptibility to UV carcinogenesis, homozygous Xpa knockout mice (deficient in nucleotide excision repair) and heterozygousp53 knockout mice (i.a. partially deficient in apoptosis). In both of these cancer-prone strains, the p53+ foci were induced at markedly increased rates, corresponding to increased rates of carcinoma formation. Therefore, the frequency of p53+ foci appears to correlate well with UVB-induced tumor risk.

Animals↗
PubMed2001

UV-induced DNA damage, repair, mutations and oncogenic pathways in skin cancer.

Repair of UV induced DNA damage is of key importance to UV-induced skin carcinogenesis. Specific signal transduction pathways that regulate cell cycling, differentiation and apoptosis are found to be corrupted in skin cancers, e.g., the epidermal growth-stimulating Hedgehog pathway in basal cell carcinomas (BCCs). Mutations in genes coding for proteins in these pathways lead to persistent disturbances that are passed along to daughter cells, e.g., mutations in the gene for the Patched (PTCH) protein in the Hedgehog pathway. Thus far only the point mutations in the P53 gene from squamous cell carcinomas and BCCs, and in PTCH gene from BCC of xeroderma pigmentosum (XP) patients appear to be unambiguously attributable to solar UV radiation. Solar UVB radiation is most effective in causing these point mutations. Other forms of UV-induced genetic changes (e.g., deletions) may, however, contribute to skin carcinogenesis with different wavelength dependencies.

Animals↗
PubMed2001

Influence of ultraviolet B exposure on immune responses following hepatitis B vaccination in human volunteers.

Exposure to ultraviolet radiation can modulate immune responses in animal and humans. Remarkably, the ultraviolet-induced immunosuppression is not restricted to the exposed skin but is also found at other body sites, i.e., systemic immunosuppression. Effects of ultraviolet radiation on infections cannot be determined by experimentation on humans, but the effects of ultraviolet on vaccination may serve as a model. Moreover, it is important in its own right to assess whether ultraviolet radiation affects vaccination responses. In this study the effect of ultraviolet B exposure on the development of immune responses after hepatitis B vaccination in human volunteers was investigated. To this end, 191 human volunteers were vaccinated against hepatitis B with the Engerix-B vaccine. Ninety-seven of them were prior to the first vaccination exposed to ultraviolet B on 5 consecutive days with one personal minimal erythema dose per day. At several time-points before and after the ultraviolet B exposure regimen and the vaccination, blood samples were taken. Parameters for specific as well as nonspecific cellular and humoral immunity were analyzed. It was demonstrated that ultraviolet B exposure prior to hepatitis B vaccination did not alter the cellular (lymphocyte stimulation test) nor the humoral (antibody titers) immune response against hepatitis B surface antigen significantly. In contrast, contact hypersensitivity to diphenylcyclopropenone was significantly suppressed after ultraviolet B exposure, as was natural killer cell activity. These latter results confirm earlier findings and demonstrate immunosuppressive effectiveness of the ultraviolet regimen. In summary, although natural killer cell activity and contact hypersensitivity responses were suppressed, the ultraviolet B radiation protocol did not alter the humoral nor the cellular immune responses against hepatitis B surface antigen after vaccination.

Adolescent↗
PubMed2000

Differential role of transcription-coupled repair in UVB-induced G2 arrest and apoptosis in mouse epidermis.

Nucleotide excision repair (NER), apoptosis, and cell-cycle regulation are major defense mechanisms against the carcinogenic effects of UVB light. NER eliminates UVB-induced DNA photolesions via two subpathways: global genome repair (GGR) and transcription-coupled repair (TCR). Defects in NER result in the human disorders xeroderma pigmentosum (XP) and Cockayne syndrome (CS), displaying severe UV sensitivity and in the case of XP, cancer proneness. We investigated the impact of deficiencies in NER subpathways on apoptosis, hyperplasia, and cell cycle progression in the epidermis of UVB-exposed CS group B (Csb(-/-)) mice (no TCR), XP group C (Xpc(-/-)) mice (no GGR), and XP group A (Xpa(-/-)) mice (no TCR and no GGR). On UVB treatment (250 J/m(2)), Xpa(-/-) and Csb(-/-) mice revealed an extensive apoptotic response in the skin, a blockage of cell cycle progression of epidermal cells, and strong hyperplasia. Interestingly, the absence of this apoptotic response in the skin of wild-type and Xpc(-/-) mice coincided with the ability of epidermal cells to enter the S phase. However, only epidermal cells of Xpc(-/-) mice subsequently became arrested in the G(2) phase. Our data demonstrate that TCR (and/or restoration of UVB-inhibited transcription) enables damaged cells to progress through S phase and prevents the induction of apoptosis and hyperplasia. G(2) arrest is manifest only under conditions of proficient TCR in combination with deficient GGR, indicating that epidermal cells become arrested in the G(2) phase as a result of persisting damage in their genome.

Animals↗
PubMed2000

Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice.

The nucleotide excision repair (NER) system is comprised of two subpathways, i.e., transcription-coupled repair (TCR) and global genome repair (GGR). To establish the relative importance of TCR and GGR for UV effects on the skin, we have used hairless knockout mouse strain lacking either TCR (CSB -/-) or GGR (XPC -/-). In single exposure experiments, we found that CSB -/- mice have a 7-16 times higher susceptibility to sunburn than XPC -/- mice and than heterozygous (+/-) and wild-type (+/+) controls. Exposure to 80 J/m2 UV radiation (i.e., suberythemogenic in CSB -/-) on 10 consecutive days gives rise to epidermal hyperplasia in CSB -/- and XPC -/-, whereas repair-proficient controls do not show epidermal hyperplasia from these exposures. In addition, CSB -/- mice develop marked parakeratosis, whereas XPC -/- mice and controls do not. Under continued exposure to this daily dose, squamous cell carcinomas appear in CSB -/-, XPC -/-, and in the control groups, whereas only in the CSB -/- animals is a fairly high number of benign papillomas also found. The median latency time of squamous cell carcinomas (diameters > or = 1 mm) is 84 days for the XPC -/- mice, 115 days for the CSB -/- mice, and 234-238 days for the heterozygous and wild-type control groups. These results indicate that GGR is more important than TCR in protection against UV-induced carcinomas of the skin but not against other UV effects such as sunburn, epidermal thickening, scaling of the stratum corneum, and development of papillomas. These results also indicate that GGR capacity may serve as a better predictor for skin cancer susceptibility than sensitivity to sunburn. The relative cancer susceptibilities of GGR- and TCR-deficient skin could well depend on the balance between an increased mutation rate and the presence (in CSB -/-) or lack (in XPC -/-) of a compensatory apoptotic response.

Animals↗
PubMed2000

Photocarcinogenesis: UVA vs UVB.

Ultraviolet B and A radiations (respective wavelength ranges 280-315 and 315-400 nm) are present in sunlight at ground level. The ultraviolet radiation does not penetrate any deeper than the skin and has been associated with various types of human skin cancers. The carcinogenicity of UVB radiation is well established experimentally and, to a large extent, understood as a process of direct photochemical damage to DNA from which gene mutations arise. Although UVA is generally far less carcinogenic than UVB radiation, it is present more abundantly in sunlight than UVB radiation (> 20 times radiant energy) and can, therefore, contribute appreciably to the carcinogenicity of sunlight. In contrast to UVB, UVA radiation is hardly absorbed by DNA. Hence, the absorption by other molecules (endogenous photosensitizers) becomes more important, thus radicals and, more specifically, reactive oxygen species can be generated that can damage DNA, membranes, and other cellular constituents. These photochemical differences between UVA and UVB radiations are reflected in differences in cellular responses and carcinogenesis.

Animals↗
PubMed1999

Mouse model for the DNA repair/basal transcription disorder trichothiodystrophy reveals cancer predisposition.

Patients with the nucleotide excision repair (NER) disorder xeroderma pigmentosum (XP) are highly predisposed to develop sunlight-induced skin cancer, in remarkable contrast to photosensitive NER-deficient trichothiodystrophy (TTD) patients carrying mutations in the same XPD gene. XPD encodes a helicase subunit of the dually functional DNA repair/basal transcription complex TFIIH. The pleiotropic disease phenotype is hypothesized to be, in part, derived from a repair defect causing UV sensitivity and, in part, from a subtle, viable basal transcription deficiency accounting for the cutaneous, developmental, and the typical brittle hair features of TTD. To understand the relationship between deficient NER and tumor susceptibility, we used a mouse model for TTD that mimics an XPD point mutation of a TTD patient in the mouse germline. Like the fibroblasts from the patient, mouse cells exhibit a partial NER defect, evident from the reduced UV-induced DNA repair synthesis (residual repair capacity approximately 25%), limited recovery of RNA synthesis after UV exposure, and a relatively mild hypersensitivity to cell killing by UV or 7,12-dimethylbenz[a]anthracene. In accordance with the cellular studies, TTD mice exhibit a modestly increased sensitivity to UV-induced inflammation and hyperplasia of the skin. In striking contrast to the human syndrome, TTD mice manifest a dear susceptibility to UV- and 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis, albeit not as pronounced as the totally NER-deficient XPA mice. These findings open up the possibility that TTD is associated with a so far unnoticed cancer predisposition and support the notion that a NER deficiency enhances cancer susceptibility. These findings have important implications for the etiology of the human disorder and for the impact of NER on carcinogenesis.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1999

Effects of chronic low-dose ultraviolet B radiation on DNA damage and repair in mouse skin.

Chronic exposure to sunlight causes skin cancer in humans, yet little is known about how habitual exposure to low doses of ultraviolet B radiation (UVB) affects DNA damage in the skin. We treated Skh-1 hairless mice with daily doses of suberythemal UVB for 40 days and analyzed the amount and distribution of DNA photodamage using RIAs and immunofluorescence micrography. We found that DNA damage accumulated in mouse skin as a result of chronic irradiation and that this damage persisted in the dermis and epidermis for several weeks after the chronic treatment was terminated. Although the persistent damage was evenly distributed throughout the dermis, it remained in the epidermis as a small number of heavily damaged cells at the dermal-epidermal boundary. Rates of DNA damage induction and repair were determined at different times over the course of chronic treatment in response to a higher challenge dose of UVB light. The amount of damage induced by the challenge dose increased in response to chronic exposure, and excision repair of cyclobutane pyrimidine dimers and pyrimidine(6-4)pyrimidone dimers was significantly reduced. The sensitization of mouse epidermal DNA to photoproduct induction, the reduction in excision repair, and the accumulation of nonrepairable DNA damage in the dermis and epidermis suggest that chronic low-dose exposure to sunlight may significantly enhance the predisposition of mammalian skin to sunlight-induced carcinogenesis.

Animals↗
PubMed1999

Skin cancer and solar UV radiation.

Ultraviolet (UV) radiation in sunlight is the most prominent and ubiquitous physical carcinogen in our natural environment. It is highly genotoxic but does not penetrate the body any deeper than the skin. Like all organisms regularly exposed to sunlight, the human skin is extremely well adapted to continuous UV stress. Well-pigmented skin is clearly better protected than white Caucasian skin. The sun-seeking habits of white Caucasians in developed countries are likely to have contributed strongly to the increase in skin cancer observed over the last century. Skin cancer is by far the most common type of cancer in the U.S.A. and Australia, which appears to be the result of an 'unnatural displacement' of people with sun-sensitive skin to sub-tropical regions. Although campaigns have been successful in informing people about the risks of sun exposure, general attitudes and behaviour do not yet appear to have changed to the extent that trends in skin cancer morbidity and the corresponding burden on public healthcare will be reversed. The relationship between skin cancer and regular sun exposure was suspected by physicians in the late 19th century, and subsequently substantiated in animal experiments in the early part of the 20th century. UV radiation was found to be highly genotoxic, and DNA repair proved to be crucial in fending off detrimental effects such as mutagenesis and cell death. In fact, around 1940 it was shown that the wavelength dependence of mutagenicity paralleled the UV absorption by DNA. In the 1970s research on UV carcinogenesis received a new impetus from the arising concern about a possible future depletion of the stratospheric ozone layer: the resulting increases in ambient UV loads were expected to raise skin cancer incidences. Epidemiological studies in the last decades of the 20th century have greatly refined our knowledge on the aetiology of skin cancers. Analyses of gene mutations in skin carcinomas have identified UV radiation as the cause. The relationship between the most fatal skin cancer, i.e. malignant melanoma and solar UV exposure is, however, still unclear and needs to be clarified to optimise preventive measures and minimise mortality from skin cancers.

DNA Damage↗
PubMed1999

CD11b+ cells and ultraviolet-B-resistant CD1a+ cells in skin of patients with polymorphous light eruption.

After ultraviolet exposure Langerhans cells (epidermal CD1a+ cells) disappear from the healthy skin, and CD11b+ macrophage-like cells, which are reported to produce interleukin-10, appear in a matter of days. These phenomena are related to the ultraviolet-induced local suppression of contact hypersensitivity reactions. A defect in this suppression might allow inadvertent immune reactions to develop after ultraviolet (over)exposure; i.e., it could cause ultraviolet-B-induced polymorphous light eruption. In order to test this we first exposed buttock skin of eight healthy volunteers to six minimal erythema doses from Philips TL12 lamps, and indeed observed a dramatic disappearance of CD1a+ cells 48 and 72 h later, at which time the number of CD11b+ cells increased in the dermis, and some occurred in the epidermis. The epidermis thickened and showed large defects, filled by CD11b+ cells, just below the stratum corneum. In 10 patients with polymorphous light eruption (five with a normal minimal erythema dose and five with a low minimal erythema dose) CD1a+ cells were present in the epidermis as well as in the dermis before exposure. Strikingly, these cells were still present in considerable number at 48 and 72 h after exposure to six minimal erythema doses. CD11b+ cells already present in the dermis before ultraviolet exposure, increased after ultraviolet exposure, and subsequently also invaded the epidermis. Despite the six minimal erythema doses, there were no apparent defects in the epidermis of the polymorphous light eruption patients. This deviant early response to ultraviolet radiation is likely to be of direct relevance to the polymorphous light eruption and is perhaps useful as a diagnostic criterion.

Adult↗
PubMed1999

Methods for exposure of laboratory animals to ultraviolet radiation.

Two different sources of ultraviolet B (UVB) radiation, an electronically controlled UVB exposure unit, containing FS40 tubes, and a hand-held Kromayer lamp, were evaluated for actual irradiance in W/m2 and spectra (physical dosimetry and biological dosimetry (skin effects in rodents)). The technical studies of the FS40 sources demonstrated that the flux intensity of the lamps could be changed electronically, without affecting the spectrum. Thus it was possible to standardize UVB exposure electronically. The biologically effective doses of these sources were analysed in RIV-Tox Wistar rats and BALB/c mice. After low doses of UVB radiation, histopathological changes such as acanthosis, hyperkeratosis and dermal inflammation were observed in the skin without the presence of major side effects such as erythema and oedema. After higher doses of UVB radiation erythema and oedema were clearly visible. Quantitative studies showed that the minimal erythema dose, as a biological parameter, correlated well to the emission in J/m2. In addition, biological parameters such as acanthosis and inflammation in the skin correlated well to the actual exposure in J/m2 and were sensitive biomarkers for UVB-induced skin toxicity. Thus, in addition to minimal erythemal doses, acanthosis and inflammation may also be applied as biologically relevant doses for studies of the biological effects of UVB radiation.

Animals↗
PubMed1999

Mutations in cancer genes of UV-induced skin tumors of hairless mice.

Ultraviolet (UV) radiation is a very common carcinogen in our environment. Epidemiological data on the relationship between skin cancers and ambient solar UV radiation are very limited. Hairless mice provide the possibility to study the process of UV carcinogenesis in more detail. Experiments with this animal model have yielded quantitative data on how tumor development depends on dose, time and wavelength of the UV radiation. In addition, at the molecular level the interactions between UV, specific cancer genes-like the Ras oncogene family and the p53 tumor suppressor gene, together with the role of DNA repair in this process have been addressed recently. In wildtype hairless mice mutations in the p53 gene are clearly linked to UVB but not to UVA radiation. Furthermore, the p53 alterations seem to be essential early in tumor development. However, in Xpa-deficient mice this dependency on p53 alterations appeared to be different as is the tumor type induced by UVB. Research using genetically modified hairless mice should enable us to further unravel the mechanisms of UV-induced skin cancer.

Animals↗
PubMed1998

XPA-deficiency in hairless mice causes a shift in skin tumor types and mutational target genes after exposure to low doses of U.V.B.

Xeroderma pigmentosum (XP) patients with a defect in the nucleotide excision repair gene XPA, develop tumors with a high frequency on sun-exposed areas of the skin. Here we describe that hairless XPA-deficient mice also develop skin tumors with a short latency time and a 100% prevalence after daily exposure to low doses of U.V.B. Surprisingly and in contrast to U.V.B.-exposed repair proficient hairless mice who mainly develop squamous cell carcinomas, the XPA-deficient mice developed papillomas with a high frequency (31%) at a U.V. dose of 32 J/m2 daily. At the highest daily dose of 80 J/m2 mainly squamous cell carcinomas (56%) and only 10% of papillomas were found in XPA-deficient hairless mice. p53 gene mutations were examined in exons 5, 7 and 8 and were detected in only 3 out of 37 of these skin tumors, whereas in tumors of control U.V.B.-irradiated wild type littermates this frequency was higher (45%) and more in line with our previous data. Strikingly, a high incidence of activating ras gene mutations were observed in U.V.B.-induced papillomas (in 11 out of 14 tumors analysed). In only two out of 14 squamous cell carcinomas we found similar ras gene mutations. The observed shift from squamous cell carcinomas in wild type hairless mice to papillomas in XPA-deficient hairless mice, and a corresponding shift in mutated cancer genes in these tumors, provide new clues on the pathogenesis of chemically- versus U.V.B.-induced skin carcinogenesis.

Animals↗