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Ethylnitrosourea-induced Development of Malignant Schwannomas in the Rat

Two Distinct Loci on Chromosome 10 Involved in Tumor Susceptibility and Oncogenesis¹

Institute of Cell Biology (Cancer Research), University of Essen Medical School and West German Cancer Center Essen, D-45122 Essen, Germany (A. K.-R., B. U. K., S. H., M. F. R.), and Institute of Human Genetics and Anthropology, University of Heidelberg, D-69120 Heidelberg, Germany (C. F.)

Inbred rodent strains with differing sensitivity to experimental tumor induction provide model systems for the detection of genes that either are responsible for cancer predisposition or modify the process of carcinogenesis. Rats of the inbred BD strains differ in their susceptibility to the induction of neural tumors by N-ethyl-N-nitrosourea (EtNU). Newborn BDIX rats that are exposed to EtNU (80 µg/g body weight; injected s.c.) develop malignant schwannomas predominantly of the trigeminal nerves with an incidence >85%, whereas BDIV rats are entirely resistant. A T:AA:T transversion mutation at nucleotide 2012 of the neu (erbB-2) gene on chromosome 10, presumably the initial event in EtNU-induced schwannoma development, is later followed by loss of the wild-type neu allele. Genetic crosses between BDIX and BDIV rats served: (a) to investigate the inheritance of susceptibility; (b) to obtain animals informative for the mapping of losses of heterozygosity (LOH) in tumors with polymorphic simple sequence length polymorphisms (SSLPs); and (c) to localize genes associated with schwannoma susceptibility by linkage analysis with SSLPs. Schwannoma development was strongly suppressed in F₁ animals (20% incidence). All of the F₁ schwannomas displayed LOH on chromosome 10, with a consensus region on the telomeric tip encompassing D10Rat3, D10Mgh16 and D10Rat2 but excluding neu. A strong bias toward losing the BDIV alleles suggests the involvement of a BDIV-specific tumor suppressor gene(s). Targeted linkage analysis with chromosome 10 SSLPs in F₂ intercross and backcross animals localized schwannoma susceptibility to a region around D10Wox23, 30 cM centromeric to the tip. Ninety-four % of F₁ 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.

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