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PubMed1975

Repair of DNA in xeroderma pigmentosum conjunctiva.

Xeroderma pigmentosum (XP) is an autosomal recessive disease with tumor formation on sun-exposed areas of the skin and eyes. Cells from most XP patients are deficient in repairing DNA damaged by ultraviolet (UV) light as shown by a reduced rate of tritiated thymidine (3HTdR) incorporation during their DNA repair synthesis. We have studied such repair synthesis in conjunctival cells from an XP patient with a conjunctival epithelioma and from normal cadaver conjunctiva. Cultured conjunctival cells were irradiated with UV light and then incubated with 3HTdR. Autoradiograms were prepared and showed that UV radiation induced a considerably slower rate of DNA repair synthesis in the XP cells than in normal cells. Many of the ocular abnormalities of XP, including tumor formation, may be the result of this defective DNA repair process.

Adolescent↗

PubMed1997

In vitro repair of oxidative DNA damage by human nucleotide excision repair system: possible explanation for neurodegeneration in xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) patients fail to remove pyrimidine dimers caused by sunlight and, as a consequence, develop multiple cancers in areas exposed to light. The second most common sign, present in 20-30% of XP patients, is a set of neurological abnormalities caused by neuronal death in the central and peripheral nervous systems. Neural tissue is shielded from sunlight-induced DNA damage, so the cause of neurodegeneration in XP patients remains unexplained. In this study, we show that two major oxidative DNA lesions, 8-oxoguanine and thymine glycol, are excised from DNA in vitro by the same enzyme system responsible for removing pyrimidine dimers and other bulky DNA adducts. Our results suggest that XP neurological disease may be caused by defective repair of lesions that are produced in nerve cells by reactive oxygen species generated as by-products of an active oxidative metabolism.

Animals↗

PubMed1999

Molecular analysis of glioma and skin-tumour alterations in a xeroderma-pigmentosum child.

Xeroderma pigmentosum (XP) is a rare hereditary disease characterized by a very high frequency of skin tumours due to a defect in the nucleotide-excision-repair process. Some of these patients have also been reported to develop internal tumours with higher frequency than the normal population. Reported here are the clinical features and molecular analysis of an XP patient who developed multiple skin cancers as well as a thalamic glioma. Complementation analysis with recombinant retrovirus, cloning efficiency and unscheduled DNA synthesis after UV-C indicate that the patient belongs to the C group. Characterization of the p53 mutations in the 2 tumours of the patient leads to speculation on the aetiological agents involved in tumour initiation. The skin tumour is clearly induced by the presence of unrepaired UVB-induced DNA damage on the non-transcribed strand of the p53 gene, while the glioma may be induced by unrepaired DNA lesions produced by free radicals.

Brain Neoplasms↗

PubMedDate not supplied

Multi-layer amniotic membrane graft for pterygium in a patient with xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare, autosomal recessive, premalignant condition of the skin, and is reported to be associated with ocular surface disorders such as conjunctival malignancy and pterygium. Herein, we report a case of successful management of pterygium with multi-layer amniotic membrane graft (AMG) in a young XP patient. CASE: An 11-year-old Japanese girl, who had been diagnosed as having XP, was referred to us for treatment of her bilateral pterygium. Surgical intervention was attempted for a temporal, presumably fast-growing pterygium in her left eye. Multi-layer amniotic membrane grafting was performed. OBSERVATIONS: The surgery-induced pain and irritation disappeared within a day. The limbal conjunctival autograft survived on the AMG and re-epithelialization over the AMG was completed in 2 weeks. Best corrected visual acuity improved from 20/32 to 20/16 one month postoperatively. During the 1-year follow-up period, no recurrence was noted. CONCLUSIONS: The present case exemplifies that AMG as an adjunct to primary pterygium resection is effective even in a young patient with XP. In addition, multi-layer AMG, which we first demonstrated in this report, seems to be useful for protecting bare sclera and extraocular muscles from mechanical injury.

Amnion↗

PubMed1980

Reduced capacity to repair irradiated adenovirus in fibroblasts from xeroderma pigmentosum heterozygotes.

Xeroderma pigmentosum (XP) is one of a number of autosomal recessive syndromes in humans characterized by a marked predisposition to cancer. Fibroblasts from these patients show a defect in DNA repair. The XP heterozygotes also show elevated skin cancer incidence, but reports concerning their DNA repair capacity are conflicting. In this study, the DNA repair capacity of four XP heterozygotes was examined using a sensitive host cell reactivation technique. Unirradiated and irradiated suspensions of adenovirus type 2 (Ad 2) were assayed for their ability to form viral structural antigens in fibroblasts from XP heterozygotes, XP homozygotes, and normals. A reduced host cell reactivation (of viral structural antigen production) for both ultraviolet- and gamma-irradiated Ad 2 was detected in four XP heterozygotes representing three different complementation groups as well as their XP homozygous children. The doses necessary to reduce the survival of viral structural antigen production by irradiated AD 2 to 37% in the XP heterozygous strains were expressed as a percentage of that obtained in normal strains and ranged from 55 to 82% for ultraviolet-irradiated Ad 2 and 71 to 79% for gamma-irradiated Ad 2. These results add further support to a direct relationship between cancer proneness and DNA repair defects and show the merits of this host cell reactivation technique in identifying XP heterozygotes. Identification of XP heterozygotes is of considerable public health interest not only in genetic counseling but also in the prevention of cancer.

Adenoviruses, Human↗

PubMed1994

Localized induction of micronuclei in the oral mucosa of xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) patients are predisposed not only to skin cancers but also to tumors on the tip of the tongue. Although this enhanced risk has been attributed to a defect in the repair of DNA damage induced by ultraviolet rays from sunlight there is a lack of data showing that DNA damage is occurring in vivo at these sites. In order to determine whether a relationship exists between exposure to ultraviolet light and the level of chromosomal breakage occurring in epithelial tissue in XP patients, the exfoliated cell micronucleus test was applied to different sites in the oral cavities of four XP patients: the right and left buccal mucosa, the dorsal tip of the tongue and the palate. Six Egyptian controls were sampled concurrently. Micronucleus (MN) frequencies were higher in XP patients than in controls for all sites except the palate, where technical difficulties were encountered. In addition, an unequal distribution of the frequency of micronucleated cells was found in the different sample sites of the oral cavity in the XP patients, with the greatest elevation in frequencies among cells collected from the dorsal tip of the tongue. In contrast, the frequency of micronucleated cells did not vary significantly in samples from different sites obtained from the controls. These data suggest that the complex interplay of host and environmental factors can affect MN frequencies when this endpoint is used to quantify in vivo genotoxic damage in a tissue.

Adult↗

PubMed1983

Stable low molecular weight DNA in xeroderma pigmentosum cells.

Xeroderma pigmentosum (XP) cells from several complementation groups contained more low molecular weight DNA upon alkaline sucrose gradient centrifugation than did other human cells examined. Under conditions in which only 5% of the DNA in normal cells sedimented at 16 S or less, 20% of the DNA in XP cells from complementation group A sedimented at 16 S or less. Because cells were layered directly onto the gradients for lysing of cells and denaturing of the DNA, it appears that this low molecular weight material is due to naturally existing gaps or alkali-sensitive sites, or both, in the cellular DNA. The increase in low molecular weight DNA seen in XP complementation group A cells also is seen in complementation groups C, D, and E. When prelabeled cells were incubated for increasing times after removal of the radioactive label, the amount of low molecular weight material remained constant over a 3-hr period. The introduction of the DNA-damaging agent, bleomycin, to prelabeled XP cells produced a surprising effect. The normal response of human cells to bleomycin is an increase in low molecular weight DNA, dependent on the dose of the drug and time of treatment. In XP cells the reverse was observed. That is, the low molecular weight DNA observed in untreated XP cells disappeared upon addition of the drug. The process responsible for the unusual response of XP cells to bleomycin is unknown, but these results are compatible with an inducible repair process.

Bleomycin↗

PubMed1993

High mutation frequency in ras genes of skin tumors isolated from DNA repair deficient xeroderma pigmentosum patients.

Xeroderma pigmentosum (XP) patients are clinically characterized by a very high incidence of skin cancers on exposed skin, at an early age. XP cells in vitro are strongly deficient in excision-repair and highly mutagenized by UV light. We were, therefore, interested in measuring mutation frequency and in determining mutation spectra in patients' tumors exposed to UV lesions. We chose to look at oncogene activation in skin tumors with the idea that more mutations, particularly of the ras gene family, would be found in XP tumors where lesions remain unrepaired compared to normal individuals. Our results clearly show that more than a 2-fold significantly higher mutation frequency (50%) of the ras genes was found in XP in contrast to control tumors (22%). The majority of the mutations were found at codon 12 of all three ras genes with a preponderance for N-ras in XP samples. The mutation spectra indicate that all mutations found were located opposite pyrimidine-pyrimidine sequences which represent a hot spot for UV-induced DNA lesions. Most of the mutations were of the type expected from studies performed in vitro with model systems. This high mutation frequency in XP was accompanied by a very high level of Ha-ras and c-myc gene amplification and rearrangement. All these data are consistent with a fundamental role of unrepaired UV-induced DNA lesions as an initiating event in human skin tumors on exposed parts of the body.

Base Sequence↗

PubMed2005

Dermoscopy of skin lesions in two patients with xeroderma pigmentosum.

BACKGROUND: Xeroderma pigmentosum (XP) is a rare disorder produced by a genetic defect in the repair of DNA damage caused by ultraviolet radiation. The early diagnosis of malignant skin tumours is crucial in the survival of patients with XP, but this is not easy even for experienced dermatologists due to the presence of a high number of actinic lesions. Dermoscopy is a new diagnostic method that increases the diagnostic accuracy for skin tumours. OBJECTIVES: To describe the clinical and dermoscopic features of different benign and malignant lesions [focusing on malignant melanoma, basal cell carcinoma (BCC) and benign melanocytic naevi] in two patients with XP. METHODS: Three dermatologists with experience in pigmented skin lesions and dermoscopy examined two siblings with XP over a period of 54 months. Diagnosis of skin tumours was obtained using clinical examination and dermoscopy with 10-fold magnification and digital images. All the tumours with criteria of malignancy were excised for further histopathological analyses. RESULTS: Multiple skin tumours showing some degree of pigmentation were detected in the patients. Clinical and dermoscopic examination allowed the discrimination of four melanomas (three of them in situ), 26 BCCs and five dysplastic naevi from other pigmented skin lesions. The features and parameters previously described for dermoscopy were shown to be appropriate for the recognition of tumours in our patients with XP. Generalized actinic lentigos were distinguished from BCCs by the presence of a delicate brown pigmented network. Fine vessels from poikiloderma were differentiated from the arborizing telangiectasia of BCC. CONCLUSIONS: The dermoscopic findings in the tumours were similar to those previously described in patients not affected by XP. Diagnosis by dermoscopic pattern analyses allowed a correct classification of malignant tumours in these cases.

Adolescent↗

PubMed2004

Brainstem and basal ganglia lesions in xeroderma pigmentosum group A.

Xeroderma pigmentosum group A (XPA) is a hereditary disorder characterized by cutaneous symptoms and progressive neurodegeneration. Since XPA patients exhibit peripheral neuropathy, neuronal deafness, rigidity, dysphagia, and laryngeal dystonia, it is indispensable for investigation of the neurodegeneration to analyze brainstem and basal ganglia lesions clinically and pathologically; we have previously shown the role of oxidative stress in the development of basal ganglia lesions. Here we immunohistochemically examined the expression of neurotransmitters, calcium-binding proteins, and neuropeptides in the brainstem, basal ganglia, and thalamus in 5 XPA autopsy cases. In the brainstem, immunoreactivity for tyrosine hydroxylase, tryptophan hydroxylase, and calbindin-D28K was severely reduced throughout the brainstem in all the XPA cases. Nevertheless, the expressions of parvalbumin, substance P, and methionine-enkephalin in the brainstem were comparatively preserved; the exception being reduced immunoreactivity for them in the cochlear and dorsal column nuclei in 3 cases. The large cell neurons in the putamen were preferentially reduced, the immunoreactivity for tyrosine hydroxylase reflecting the dopaminergic afferent and efferent pathways was severely affected, and the expression of 3 calcium binding proteins (i.e. parvalbumin, calbindin-D28K, and calretinin) was disturbed in various ways. The expression of substance P and methionine-enkephalin, which are involved in the efferent pathways in the basal ganglia, in the globus pallidus and substantia nigra was spared. It is speculated that the selective damage to the dopamine system in the basal ganglia and the disturbed monoaminergic expression in the brainstem could be related to clinical abnormalities such as the rigidity, laryngeal dystonia, and several neurophysiological changes. Functional analysis of autopsy brains will facilitate clarification of the pathogenesis of the neurodegeneration in XPA.

Adolescent↗

PubMed2005

Reduced XPC DNA repair gene mRNA levels in clinically normal parents of xeroderma pigmentosum patients.

Xeroderma pigmentosum group C (XP-C) is a rare autosomal recessive disorder. Patients with two mutant alleles of the XPC DNA repair gene have sun sensitivity and a 1000-fold increase in skin cancers. Clinically normal parents of XP-C patients have one mutant allele and one normal allele. As a step toward evaluating cancer risk in these XPC heterozygotes we characterized cells from 16 XP families. We identified 15 causative mutations (5 frameshift, 6 nonsense and 4 splicing) in the XPC gene in cells from 16 XP probands. All had premature termination codons (PTC) and absence of normal XPC protein on western blotting. The cell lines from 26 parents were heterozygous for the same mutations. We employed a real-time quantitative reverse transcriptase-PCR assay as a rapid and sensitive method to measure XPC mRNA levels. The mean XPC mRNA levels in the cell lines from the XP-C probands were 24% (P<10(-7)) of that in 10 normal controls. This reduced XPC mRNA level in cells from XP-C patients was caused by the PTC that induces nonsense-mediated mRNA decay. The mean XPC mRNA levels in cell lines from the heterozygous XP-C carriers were intermediate (59%, P=10(-4)) between the values for the XP patients and the normal controls. This study demonstrates reduced XPC mRNA levels in XP-C patients and heterozygotes. Thus, XPC mRNA levels may be evaluated as a marker of cancer susceptibility in carriers of mutations in the XPC gene.

Adolescent↗

PubMed2001

Enhanced S phase delay and inhibition of replication of an undamaged shuttle vector in UVC-irradiated xeroderma pigmentosum variant.

Xeroderma pigmentosum variant (XP-V) cells are defective in bypass replication of UVC-induced thymine dimers in DNA because they lack a novel DNA polymerase (polymerase eta). In this study the effects of UVC on S phase cells were compared in fibroblasts derived from normal donors (IDH4) and XP-V patients (CTag) and immortalized by expression of the SV40 large T antigen. These transformed fibroblasts did not activate the G(1) checkpoint or inhibit replicon initiation when damaged by UVC or gamma-rays. The transformed XP-V cells (CTag) retained the increased sensitivity to UVC-induced inhibition of DNA strand growth previously observed with their diploid counterpart. Cell cycle progression analyses showed that CTag cells displayed a stronger S phase delay than transformed fibroblasts from normal individuals (IDH4) after treatment with only 2 J/m(2) UVC. Low doses of UVC also caused a lag in CTag cell proliferation. The extent of replication of an episomal DNA (pSV011), not previously exposed to radiation, was measured after the host cells were irradiated with 1-3 J/m(2) UVC. Replication of pSV011 was barely affected in irradiated IDH4 cells. Plasmid replication was inhibited by 50% in irradiated CTag cells and this inhibition could not be accounted for by increased killing of host cells by UVC. These results suggest that even in transformed cells UVC induces DNA damage responses that are reflected in transient cell cycle arrest, delay in proliferation and inhibition of episomal DNA replication. These responses are enhanced in CTag cells, presumably because of their bypass replication defect. The accumulation of replication complexes blocked at thymine dimers and extended single-stranded regions in chromosomal DNA might sequester replication factors that are needed for plasmid and chromosomal replication. Alternatively, aberrant replication structures might activate a signal transduction pathway that down-regulates DNA synthesis.

Antigens, Polyomavirus Transforming↗

PubMed2005

Xeroderma pigmentosum group E and DDB2, a smaller subunit of damage-specific DNA binding protein: proposed classification of xeroderma pigmentosum, Cockayne syndrome, and ultraviolet-sensitive syndrome.

Xeroderma pigmentosum is a rare photosensitive syndrome that comprises eight different genetic diseases (A to G; variant (V)). Although genotype-phenotype correlations have been evaluated in most XP groups, the relationship between the E subgroup of xeroderma pigmentosum (XP-E) and damage-specific DNA binding protein (DDB) still remained a mystery. Recent studies have provided new insight for XP-E and the role(s) of DDB2, a smaller subunit of DDB. Reclassification studies have confirmed that mutations in DDB2 give rise to XP-E. The mouse model of XP-E demonstrated that DDB2 was well conserved between mouse and human and was critical in controlling proper cell-survival through regulating the tumor suppressor p53-mediated responses after ultraviolet (UV)-irradiation: i.e. defective DDB2 causes the resistance to cell-killing by UV-irradiation due to decreased p53-mediated apoptosis. These phenotypes are unique to XP-E because other XP groups show normal (XP-V) or hypersensitivity (XP-A, B, C, D, F, and G) to UV-irradiation. Thus XP-E is defined as a skin cancer prone disease with unique resistance to UV-irradiation.

Animals↗

PubMed2003

Differential UVC-induced gadd45 gene expression in xeroderma pigmentosum cells.

Xeroderma pigmentosum C (XPC) is a DNA repair factor essential for global genome repair (GGR) in nucleotide excision repair (NER). In the present study we screened for factors regulated by XPC after DNA damage. Ultraviolet C (UVC) irradiation-induced stress response factors were analyzed by a cDNA microarray chip system in HeLa and XP4PA-SV xpc mutant cell lines. The principal component analysis (PCA) method was employed to identify groups of genes with similar expression patterns over time after UVC irradiation. The growth arrest and DNA damage-inducible gene gadd45, as well as a small group of other genes, was found to exhibit an inducible expression pattern after 30min of incubation in xpc mutants but not in HeLa cells. Subsequent studies showed that gadd45 gene expression post-UVC irradiation was also present in the GGR mutant cells xpa and xpd, but not in TCR mutant csb cells. This evidence indicates that gadd45 plays a regulatory role in GGR of NER.

Cell Line↗

PubMed1997

[Xeroderma pigmentosum].

MAIN CLINICAL FEATURES: Xeroderma pigmentosum is a rare, recessive disorder clinically characterized by extreme photosensitivity, pigmented abnormalities of the skin-exposed areas, and frequent ocular and neurological abnormalities. Xeroderma pigmentosum syndrome is associated with an estimated 2000-fold increase in the risk to develop skin cancer (basal cell carcinoma, squamous cell carcinoma and melanoma). A HETEROGENEOUS DISEASE: Skin or blood cells from Xeroderma pigmentosum patients are hypersensitive to killing by ultraviolet and hypermutable after ultraviolet C treatment Cell fusion experiments based on complementation of repair synthesis have recognized the presence of seven Xeroderma pigmentosum groups which exhibit various defects in the initial steps of the DNA nucleotide excision repair pathway. A variant Xeroderma pigmentosum form has been found to be normal in nucleotide excision repair but abnormal in a poorly to be normal in nucleotide excision repair but abnormal in a poorly understood postreplication repair process. PATHOPHYSIOLOGY: The Xeroderma pigmentosum complementation groups differ in terms of severity of clinical, cellular and genetic features. Molecular and biochemical studies of the Xeroderma pigmentosum syndrome have led to a better understanding of the mechanisms of ultraviolet-induced sensitivity and the mechanism of cancer development after ultraviolet exposure.

Humans↗

PubMed2001

[Melanoma in xeroderma pigmentosum: 12 cases].

BACKGROUND: Xeroderma pigmentosum is a rare genodermatosis, with a defect affecting recovery of ultraviolet-induced damages and characterized by a high rate of malignancies of the exposed skin areas. We studied melanoma features of patients with xeroderma pigmentosum. PATIENTS AND METHODS: A retrospective study of xeroderma pigmentosum patients admitted to the Charles Nicolle Hospital of Tunis between 1973 and 1998. RESULTS: Two hundred sixteen patients with xeroderma pigmentosum were registered. Melanoma was present in 12 patients, 7 females and 5 males. Two patients were sisters. Cutaneous melanoma was found in 8 patients. Four patients presented with metastatic melanoma. The median age for development of the first melanoma was 17.5 years. All of the cutaneous melanomas were found on the face. Lentigo malignant melanoma was reported in 3 cases. The tumors were treated with surgical excision. Except for a melanoma affecting the orbit, characterized by a fatal outcome, no metastases were detected at the different investigations. DISCUSSION: Melanoma occurs frequently in patients with xeroderma pigmentosum, it has been reported in 5.5 p. 100 of cases and 11.3 p. 100 of patients with cutaneous carcinoma. The age of onset was low: 17.5 years. It appeared later than the carcinoma. The location of cutaneous melanoma in face in xeroderma pigmentosum patients indicates that they were caused mainly by sunlight exposure. Lentigo malignant melanoma was the most frequent type. Prognosis is difficult to define owing to the large number of other cutaneous malignancies. Apart from one case of rapidly fatal orbital melanoma, we recorded long survivals even in cases of melanoma revealed by metastases.

Adolescent↗

PubMed2003

[Xeroderma pigmentosum: children of the moon].

Xeroderma pigmentosum is based on a genetic defect in the DNA repair system, which is diagnosed in early childhood. Xeroderma pigmentosum is a rare disorder, which is transmitted in an autosomal recessive manner. Children with xeroderma pigmentosum display hypersensitivity to ultraviolet (UV) radiation. These patients experience serious sunburns with minimal exposure and then develop poikiloderma in the sun-exposed areas. Squamous cell carcinomas, basal cell carcinomas and malignant melanomas all appear during childhood. The majority of patients do not reach adult, but die from metastatic cutaneous malignancies. Genetically, xeroderma pigmentosum is differentiated into 7 complementation groups (XP-A to XP-G) and the xeroderma pigmentosum variants (XP-V). The assignment to the specific complementation group is made by fusing of xeroderma pigmentosum fibroblasts. Xeroderma pigmentosum must be distinguished from other so-called DNA repair deficiency syndromes, including Cockayne syndrome and trichothiodystrophy. A topical DNA repair enzyme appears to be helpful. A recombinant liposomal encapsulated T4 endonuclease V repairs UV-induced cyclobutane-pyrimidine dimers. Direct curative treatment of xeroderma pigmentosum could be achieved with gene therapy in future. Transfection of an intact repair gene which specifically codes for the missing repair protein could open new possibilities in the therapy of xeroderma pigmentosum.

Child↗

PubMed2002

Germline and somatic mutations of the INK4a-ARF gene in a xeroderma pigmentosum group C patient.

Xeroderma pigmentosum is an inheritable autosomal recessive DNA repair deficient syndrome characterized by a high predisposition to skin cancers. An elevated proportion of tumors from xeroderma pigmentosum patients harbor ultraviolet-induced mutations (CC:GG > TT:AA tandem transitions) of the p53 and/or the INK4a-ARF genes. Here, we report the clinical and molecular features of a 12 y old xeroderma pigmentosum patient who, in addition to severe cutaneous clinical symptoms, also had three unusual tumors, a mediastinal lymphoblastic lymphoma, an atypical fibroxanthoma, and an epithelioid hemangioma. Single strand conformation polymorphism and sequencing analysis of the p53 and INK4a-ARF genes were carried out in DNA from normal skin and different tumors (four actinic keratosis, two microinvasive squamous cell carcinomas, one basal cell carcinoma, and one atypical fibroxanthoma) from the patient. After characterization of the xeroderma pigmentosum C complementation group, we found unexpectedly that this patient also carried a germline mutation of the INK4a-ARF locus affecting the p16INK4A reading frame. Three different somatic mutations that all harbor the signature of ultraviolet light (two of p16INK4A and one of p53) were also detected in the basal cell carcinoma. We hypothesize that the germline mutation of p16INK4A, in association with the nucleotide excision repair defect, could explain the patient's unusual phenotype. Furthermore, this study confirms that concomitant somatic mutations of INK4a-ARF and p53 occur in some xeroderma pigmentosum associated tumors, and seem to accumulate during tumor progression rather than the initiation step.

Basal Cell Carcinoma↗