Early Mutation of the neu (erbB-2) Gene During Ethylnitrosourea-Induced Oncogenesis in the Rat Schwann Cell Lineage

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 88; no. 22; pp. 9939 - 9943
• Main Authors: Alexander Yu. Nikitin, Leo A. P. Ballering, Lyons, John, Rajewsky, Manfred F.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.11.1991; National Acad Sciences
• Subjects: Alleles; Animals; Base Sequence; Biological and medical sciences; Cell Line; Cell lines; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic; Cells; DNA, Neoplasm - analysis; Ethylnitrosourea - pharmacology; Fundamental and applied biological sciences. Psychology; Genetic mutation; Molecular and cellular biology; Molecular Sequence Data; Mutagenesis; Neurilemmoma; Neurilemmoma - genetics; Neurilemmoma - pathology; Neurons; Polymerase chain reaction; Polymorphism, Restriction Fragment Length; Protein-Tyrosine Kinases - genetics; Proto-Oncogene Proteins - genetics; Proto-Oncogenes; Rats; Rats, Inbred Strains; Receptor, ErbB-2; Schwann Cells; Tumor cell line; Tumors; Nervous system diseases; Rat; Tumor promotor; Rodentia; Mutagen; Carcinogenesis; Polymerase chain reaction; Vertebrata; Specificity; Mammalia; Cell line; Restriction fragment length polymorphism; Trigeminal nerve; Schwann cell; Mutation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.88.22.9939

The development of malignant tumors of the peripheral nervous system (schwannomas) within a defined intracranial section of the rat trigeminal nerve ("trigeminal box") was used as a model to identify genetic alterations typically associated with the process of cell-lineage-specific oncogenesis induced by exposure to N-ethyl-N-nitrosourea on postnatal day 1. All 47 trigeminal schwannomas (and 12 extracranial neurinomas) investigated carried a T·A → A·T transversion mutation at nucleotide 2012 of the neu (erbB-2) gene sequence encoding the transmembrane domain of gp185neu. This mutation was absent in all 18 tumors in the brain and spinal cord (central nervous system) isolated from the same animals. Identical observations were made in cell lines derived from N-ethyl-N-nitrosourea-induced rat schwannomas vs. brain tumors. By asymmetric PCR and mutant-specific Mnl I restriction fragment length analyses, cells carrying the mutant neu allele became detectable and could be localized within the trigeminal box as early as 7 days after the carcinogen pulse. The proliferation rate of the mutant cells strongly exceeded that of the wild-type cells up to the time of maturation of the trigeminal nerve around postnatal day 30 and thereafter to a lesser extent until the appearance of schwannomas. A specific mutation of the neu gene thus represents a very early, probably the first, step in the malignant conversion of immature rat Schwann cells exposed to N-ethyl-N-nitrosourea in vivo and is diagnostic for a subset of proliferative cells at high risk of progressing toward the expression of fully malignant phenotypes. Loss of heterozygosity for the mutant neu allele is a candidate event for a critical second step in the process.