Ethylnitrosourea-induced development of malignant schwannomas in the rat: Two distinct loci on chromosome 10 involved in tumor susceptibility and oncogenesis

Inbred rodent strains with differing sensitivity to experimental tumor indu ction provide model systems for the detection of genes that either are resp onsible for cancer predisposition or modify the process of carcinogenesis. Rats of the inbred ED strains differ in their susceptibility to the inducti on of neural tumors by N-ethyl-N-nitrosourea (EtNU), Newborn BDIX rats that are exposed to EtNU (80 mu g/g body weight; injected s.c.) develop maligna nt schwannomas predominantly of the trigeminal nerves with an incidence >85 %, whereas BDIV rats are entirely resistant. A T:A-->A:T transversion mutat ion at nucleotide 2012 of the neu (erbB-2) gene on chromosome 10, presumabl y the initial event in EtNU-induced schwannoma development, is later follow ed by loss of the wild-type neu allele, Genetic crosses between BDIX and BD IV rats served: (a) to investigate the inheritance of susceptibility; (b) t o obtain animals informative for the mapping of losses of heterozygosity (L OH) in tumors with polymorphic simple sequence length polymorphisms (SSLPs) ; and (c) to Localize genes associated with schwannoma susceptibility by li nkage analysis with SSLPs, Schwannoma development was strongly suppressed i n F-1 animals (20% incidence). All of the F-1 schwannomas displayed LOH on chromosome 10, with a consensus region on the telomeric tip encompassing D1 0Rat3 D10Mgh16 and D10Rat2 but excluding neu. A strong bias toward Losing t he BDIV alleles suggests the involvement of a BDIV-specific tumor suppresso r gene(s), Targeted linkage analysis with chromosome 10 SSLPs in F-2 interc ross and backcross animals localized schwannoma susceptibility to a region around D10Wox23, 30 cM centromeric to the tip, Ninety-four % of F-1 tumors exhibited additional LOH at this region, Two distinct loci on chromosome 10 may thus be connected with susceptibility to the induction and development of schwannomas in rats exposed to EtNU.