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Activated oncogenes in human skin tumors from a repair-deficient syndrome, xeroderma pigmentosum
H G Suarez1, L Daya-Grosjean, D Schlaifer
1Institut de Recherches Scientifiques sur le Cancer, Villejuif, France.
Abstract:
The recessive autosomal hereditary disease, xeroderma pigmentosum (XP), is characterized by a high incidence of tumors in sun-exposed skin. The defect in early steps of excision repair of XP cells leads to hypermutability towards UV-mimicking agents. DNA from eight XP tumors were screened for activated transforming genes using 3T3 transfection. In two skin tumors isolated from a XP child, an activated N-ras oncogene was detected. Synthetic oligonucleotide probes were used to characterize the mutation in the ras gene. Both tumors were found to be mutated in the 61st N-ras codon from gln to his. The mutation was accompanied by an increase in the level of N-ras specific mRNA and in one transformant, by the alteration of the p21 protein. In the same tumors, c-myc amplification and over transcription, and Ha-ras gene rearrangement and amplification were also detected. Analysis of other XP tumors with eleven different oncogene probes revealed an amplification of the Ha-ras gene in 6 out of 10 cases. The normal skin fibroblasts from XP patients show normal pattern levels of N-ras, c-myc and Ha-ras sequences. The hypothesis is proposed that the presence of several oncogene alterations in the same tumor could be due to the high amount of UV-induced DNA lesions found in the exposed skin cells, in the absence of efficient repair.
Insights
Xeroderma pigmentosum (XP) patients exhibit increased skin tumor risk due to DNA repair defects. This study found activated N-ras oncogenes and other genetic alterations in XP tumors, likely caused by unrepaired UV damage.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Xeroderma pigmentosum (XP) is an autosomal recessive disorder with high skin cancer incidence.
- XP cells have defective DNA excision repair, leading to UV-induced DNA damage accumulation and hypermutability.
- Oncogene activation is a key mechanism in cancer development.
Purpose of the Study:
- To investigate the presence and types of activated oncogenes in tumors from XP patients.
- To understand the molecular mechanisms underlying increased cancer risk in XP.
Main Methods:
- Screening of XP tumor DNA for activated transforming genes using 3T3 transfection.
- Characterization of ras gene mutations using synthetic oligonucleotide probes.
- Analysis of oncogene amplification and transcription (N-ras, c-myc, Ha-ras) via gene probes and mRNA levels.
Main Results:
- Activated N-ras oncogene detected in two skin tumors from an XP child, with a specific mutation at codon 61 (gln to his).
- Increased N-ras mRNA levels and p21 protein alteration observed in tumors with N-ras mutation.
- c-myc amplification/overexpression and Ha-ras gene rearrangement/amplification found in the same tumors.
- Ha-ras gene amplification detected in 6 out of 10 additional XP tumors.
Conclusions:
- The study identifies specific oncogene alterations (N-ras, c-myc, Ha-ras) in XP-associated skin tumors.
- These alterations are likely a consequence of unrepaired UV-induced DNA damage, contributing to XP's high cancer incidence.
- Defective DNA repair in XP patients creates a permissive environment for oncogene activation and tumor formation.