NEU MUTATIONS AND LOSS OF NORMAL ALLELE IN SCHWANNOMAS INDUCED BY N-ETYL-N-NITROSOUREA IN RATS

The mutational activation of the neu proto-oncogene was analyzed in sc hwannomas of the peripheral nervous system transplacentally induced by N-ethyl-N-nitrosourea (ENU) in rats. All nine primary schwannomas inv estigated contained a T-->A transversion mutation at nucleotide 2012 o f the neu gene, leading to the substitution of valine to glutamic acid in the transmembrane domain. Loss of the wild-type allele occurred in five of nine (56%) primary schwannomas. All four ENU-induced schwanno mas transplanted in syngenic hosts (2-14 passages) showed the T-->A tr ansversion mutation and loss of the wild-type allele. These data sugge st that mutation of one allele together with loss of the wild-type all ele constitutes two critical steps in the progression of rat schwannom as. Since c-erbB-2, the human counterpart of the rat neu gene is frequ ently involved by amplification in the development of human gastric ca ncer [30], we screened 12 rat gastric carcinomas induced by N-methyl-N -nitrosourea (MNU) for mutations in the neu gene. However, none of the se tumors contained mutations.