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Activated Oncogenes in Human Skin Tumors from a Repair-deficient Syndrome, Xeroderma Pigmentosum¹

Institut de Recherches Scientifiques sur le Cancer, B.P. no. 8, 94802—Villejuif, France [H. G. S., L. D-G., D. S., P. N., G. R., A. S.], and the Dept of Medical Biochemistry, Sylvius Laboratories, P. O. Box 9503, 2300 RA, Leiden, Holland [J. L. B.]

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.

¹ This work has been supported by grants to H. Suarez and A. Sarasin from the Association pour la Recherche sur le Cancer (Villejuif, France), from the Fondation pour la Recherche Médicale (Paris, France), from C.N.R.S. (95-9040), and from the Commission of the European Communities (BI6-163-F, Brussels, Belgium).

² To whom requests for reprints should be addressed.

Received 6/ 7/88. Revised 9/16/88. Accepted 11/ 8/88.

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