Activated oncogenes in human skin tumors from a repair-deficient syndrome, xeroderma pigmentosum.
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.
Suarez
H G
HG
Institut de Recherches Scientifiques sur le Cancer, Villejuif, France.
Daya-Grosjean
L
L
Schlaifer
D
D
Nardeux
P
P
Renault
G
G
Bos
J L
JL
Sarasin
A
A
D004247:DNA / Q000032:analysis; D004260:DNA Repair; D005784:Gene Amplification; D005786:Gene Expression Regulation; D006801:Humans; D009693:Nucleic Acid Hybridization; D011518:Proto-Oncogene Proteins / Q000032:analysis; D016283:Proto-Oncogene Proteins p21(ras); D011519:Proto-Oncogenes; D012878:Skin Neoplasms / Q000235:genetics*; D014158:Transcription, Genetic; D014983:Xeroderma Pigmentosum / Q000235:genetics*
D011518:Proto-Oncogene Proteins; D004247:DNA; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)