Allele-specific losses of heterozygosity on chromosomes 1 and 17 revealed by whole genome scan of ethylnitrosourea-induced BDIX x BDIV hybrid rat gliomas

The induction of neural tumors by N-ethyl-N-nitrosourea (EtNU) in inbred st rains of rats has evolved as a valuable model system of developmental stage - and cell type-dependent oncogenesis. Tumor yield and latency times are st rongly influenced by genetic background. Compared with BDIX rats, BDIV rats are relatively resistant to the induction of brain tumors by EtNU, with a tower tumor incidence and latency periods prolonged by a factor of 3. To ch aracterize genetic abnormalities associated with impaired tumor suppressor gene function in neuro-oncogenesis, losses of heterozygosity (LOHs) and mic rosatellite instability (MI) were investigated in brain tumors induced by E tNU in (BDIV x BDIX) F-1 and F-2 rats. The polymerase chain reaction was us ed to amplify 55 polymorphic microsatellite markers spanning the entire rat genome. The tumors displayed different histologies and grades of malignanc y, corresponding to part of the spectrum of human gliomas. Mi was not obser ved in any of the tumors. LOH of rat chromosome Iq was predominantly detect ed in oligodendrogliomas and mixed gliomas, with a 30% incidence in informa tive cases. 11p15.5, the human genome region syntenic to the consensus regi on of LOHs observed on rat chromosome 1, has been shown to be involved in t he formation of gliomas in humans. Furthermore, rat brain tumors of differe nt histologies often showed allelic imbalances on chromosome 17p. In both c ases of LOH, there was a clear bias in favor of the parental BDIV allele, s uggesting the involvement of tumor suppressor genes functionally polymorphi c between the two rat strains. (C) 1999 Wiley-Liss, Inc.