INFREQUENT TRANSFORMING MUTATIONS IN THE TRANSMEMBRANE DOMAIN OF THE NEU ONCOGENE IN SPONTANEOUS RAT SCHWANNOMAS

Ethylnitrosourea (ENU) given transplacentally to rats induces schwanno mas of the cranial, spinal, and peripheral nerves, with a high frequen cy of mutations in the neu proto-oncogene. To establish the requiremen t for such mutations in tumorigenesis of the Schwann cell, spontaneous schwannomas from BD-Vl rats were evaluated for transforming mutations in the transmembrane domain of the protein encoded by the neu protoon cogene. While all five schwannomas induced transplacentally with ENU w ere shown to contain T-->A transversions in base 2012 of neu by select ive oligonucleotide hybridization and dideoxy sequencing of polymerase chain reaction-amplified products from paraffin sections, only one of nine spontaneous schwannomas from untreated rats had the same mutatio n. Examination of tumors for mutations in codon 12 of Ki-ras revealed normal alleles. Therefore, the high frequency of mutations in neu in E NU-induced tumors may be directly attributable to the carcinogen or to the period of development at which exposure occurred, and transformin g mutations of the transmembrane domain of neu are not required for tu morigenesis of the Schwann Cell. (C) 1994 Wiley-Liss, Inc.