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neu Proto-oncogene Mutation Is Specific for the Neurofibromas in a N-Nitroso-N-ethylurea-induced Hamster Neurofibromatosis Model but not for Hamster Melanomas and Human Schwann Cell Tumors¹

Department of Pathology, Faculty of Medicine, University of Tokyo, Tokyo, Japan [T. N, T. I.]; Carcinogenesis Division, National Cancer Center Research Institute, Tokyo, Japan [T. U., Y. I., M. N.]; Department of Pathology, Faculty of Medicine, Tokyo Medical and Dental University, Tokyo, Japan [T. N.]; and Department of Pathology, Toranomon Hospital, Tokyo, Japan [M. H.]

² To whom requests for reprints should be addressed, at Mammalian Genetics Laboratory, ABL Basic Research Program, National Cancer Institute Frederick Cancer Research and Development Center, Box B, Frederick, MD 21702-1201.

Point mutations of the transmembrane domain coding region of the neu proto-oncogene in N-nitroso-N-ethylurea-induced hamster neurofibromas were found at high frequency (93%; 14 of 15). They involved codons 659 as well as 658, the latter not having been reported previously in rat tumors. The mutational change was seen even in the early stage neurofibroma. On the other hand, no mutations were detected in melanomas or Wilms' tumors induced in the same N-nitroso-N-ethylurea-treated animals, even when the melanomas demonstrated extensive schwannian differentiation. Moreover, any human Schwann cell tumors including neurofibroma, schwannoma, and malignant schwannoma did not show the mutation of c-erbB-2 gene (0 of 34), which is homologous to the hamster neu. Since high expression of neu mRNA is evident in the hamster Schwann cell at the late gestational and neonatal stages, transplacental administration of N-nitroso-N-ethylurea is considered to interact directly to carcinogenesis of the hamster Schwann cell through neu gene mutation.

¹ The research was supported in part by Grants-in-aid for Scientific Research and Cancer Research from the Ministry of Education, Science and Culture, Japan, and from the Smoking Research Foundation, Japan.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 8/ 2/93. Accepted 12/15/93.

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