Mutations in DNA polymerase eta are not detected in squamous cell carcinoma of the skin

The major etiological agent in skin cancer is exposure to UV-irradiation and the concomitant DNA damage. UV-induced DNA lesions, such as thymine dimers, block DNA synthesis by the major DNA polymerases and inhibit the progression of DNA replication. Bypass of thymine dimers and related lesions is dependent on the translesion polymerase DNA polymerase eta (Poleta). In the inherited disorder, xeroderma pigmentosum variant (XPV), inactivation of Poleta results in extreme sensitivity to UV light and a marked increase in the incidence of skin cancer. Here, we tested the hypothesis that somatic mutations and/or polymorphisms in the POLH gene that encodes Poleta are associated with the induction of UV-dependent skin cancers. We sequenced the exonic regions of the Poleta open reading frame in DNA from 17 paired samples of squamous cell skin carcinoma and adjacent histologically normal tissue. We analyzed approximately 120,000 nucleotides and detected no mutations in POLH in the tumors. However, we identified 6 different single-nucleotide polymorphisms, 3 of them previously undocumented, which were present in both the tumor and paired normal tissue. We conclude that neither mutations nor polymorphisms in the coding regions of POLH are required for the generation of human skin squamous cell carcinoma.     

Erythema dyschromicum perstans/ashy dermatosis--a report of eight cases from Singapore

Eight patients with erythema dyschromicum perstans (ashy dermatosis) are described. The characteristic ashy macules occurred mainly on the trunk and limbs. The condition did not appear to be associated with infection or drug ingestion. Seven patients had preceding erythema before onset of ashy macules; three had urticarial eruptions associated with the early erythema. Biopsy consistently showed mild, superficial, perivascular mononuclear cell infiltration and abundant melanophages in all the patients. In five, vascuolar degeneration of the basal epidermal cells was evident. There was no evidence to suggest that the condition was associated with lichen planus. The dermatosis appeared to run a prolonged course.     

Allelic heterogeneity in Group A xeroderma pigmentosum

The molecular basis of Group A xeroderma pigmentosum was investigated by restriction fragment length polymorphism analysis of PCR-amplified DNA sequences using the two restriction enzymes, endonucleases AlwN I and Hph I. The clones of a patient with Group A xeroderma pigmentosum who had typical symptoms showed a G-C substitution at the 3' splice acceptor site of intron 3. However, of the two atypical Group A xeroderma pigmentosum patients with mild skin lesions and minimal neurological abnormalities, the milder one showed homozygosity for the nonsense mutation of exon 6, while the other patient with slightly greater central nervous involvement was shown to be a compound heterozygote for the splicing mutation of intron 3 and the nonsense mutation of exon 6, thus indicating an allelic heterogeneity in group A xeroderma pigmentosum.     

Nitrofurantoin damages DNA of human cells

Summary Nitrofurantoin causes damage to DNA of cultured diploid human fibroblasts. As a consequence DNA synthesis is blocked. The damage is removed by the normal enzymatic DNA repair system. Xeroderma pigmentosum fibroblasts which are defective in the excision endonuclease fail to repair nitrofurantoin-caused lesions.     

Genetische Faktoren bei der Entstehung und Progression maligner Melanome

Zusammenfassung Die Exposition der Haut mit ultravioletten Strahlen ist ein wichtiger Risikofaktor für die Entwicklung eines malignen Melanoms. M?glicherweise spielt hierbei UVA-A eine besondere Rolle. Daneben sind heredit?re Faktoren von Bedeutung. W?hrend beim Syndrom der dysplastischen N?vi eine genetische Instabilit?t mit verschiedenen Methoden nachgewiesen wurde, wird bei Xeroderma pigmentosum der DNA-Reparaturdefekt für die hohe Melanominzidenz verantwortlich gemacht. In Melanomzellen sind überzuf?llig h?ufig karyotypische Ver?nderungen in bestimmten Chromosomen gefunden worden. Diese enthalten m?glicherweise Melanomwachstumsregulierende Sequenzen oder Melanom-Suppressorgene. Insbesondere der kurze Arm des Chromosoms 9 steht in Verdacht, eines dieser Gene zu enthalten. Diese Hypothese wird auch unterstützt durch eine genetische Kopplungsanalyse an Melanomfamilien und dem Nachweis einer Keimbahndeletion des Lokus 9p21 bei einer Patientin mit 8 prim?ren Melanomen. Ver?nderungen an bereits bekannten Tumorsuppressorgenen oder Onkogenen sind ebenfalls in Melanomen beschrieben worden, ohne da? jedoch eine konsistente Reihenfolge von genetischen Ereignissen bekannt w?re. Eingegangen am 21. M?rz 1994 Angenommen am 16. August 1994     

Heat-labile glucose-6-phosphate dehydrogenase in cultured fibroblasts from patients with De Sanctis-Cacchione syndrome

Summary The normal senescent fibroblasts in culture accumulate a significantly high proportion of altered enzymes, and the alterations are considered to be the manifestation of ageing in molecular terms. To detect the possible molecular alterations in patients with De Sanctis-Cacchione syndrome, the severest form of xeroderma pigmentosum, in which repair processes to UV light-damaged DNA are defective and the neurologic abnormalities are considered to reflect accelerated ageing, we studied the heat stability of glucose-6-phosphate dehydrogenase (G6PD) in crude extracts of cultured skin fibroblasts. Three patients with the syndrome were the center of our investigation. Even at early passage in culture the heat-labile portion of G6PD was increased in the cells from patients in comparison to normal controls.The life span of the cells in culture from patients was not reduced below normal age-matched controls, and no appreciable senescent appearance was observed. The increase in the heat-labile portion of G6PD from cells of De Sanctis-Cacchione syndrome patients to reflect that defective repair of DNA damage occurs, rather than being a direct result of ageing of cultured cells.     

Xeroderma pigmentosum and keratoconus

Two XP patients are presented. A corneal perforation in the left eye of the first patient necessitated an at-random transplantation à chaud. The graft was remarkably well tolerated, which is possibly explained by UV-light-induced suppression of the cellular immune response in the patient. The right eye of this patient and both eyes of the second patient had a keratoconus. Keratoconus in XP may be the result of disturbances in the cell differentiation and the function of epithelial cells and keratocytes, due to UV-light-induced deficient DNA repair synthesis.     

Group D Xeroderma Pigmentosum: A Case with a Number of Nevocellular Nevi

A 12-year-old boy was diagnosed as having group D xeroderma pigmentosum based on the results of unscheduled DNA synthesis (UDS) tests and complementation tests. More than 200 moles were distributed all over his body, including the unexposed areas of his torso and scalp. All of eight removed specimens were compatible histologically with nevocellular nevi.     

Trichodysplasia-xeroderma: an autosomal dominant condition

We describe six generations of a family with an autosomal dominant condition combining different degrees of trichodysplasia and xeroderma.