Alterations at the Ink4a locus in transplacentally induced murine lung tumors

The malignant phenotype results from multiple genetic alterations, includin g the activation of oncogenes and inactivation of tumor suppressor genes. A ctivation of the Ki-ras oncogene has been implicated as an early event in t he pathogenesis of lung adenocarcinomas in humans and experimental animal m odels. Previous studies from this laboratory have shown that, following tre atment of pregnant [D2 X B6D2F(1)]F-2 or Balb/c mice with the polycyclic ar omatic hydrocarbon, 3-methylcholanthrene (MC), lung tumors from the transpl acentally exposed offspring exhibited a high incidence of mutations in the Ki-ras gene. The role of genetic alterations at other oncogenic or tumor su ppressor loci that can mediate lung tumor initiation and/or progression hav e not been well characterized in either human or murine models. Using the t ransplacental carcinogenesis model, which results in the induction of both lung and liver tumors following in utero exposure to NIC, the results of th is and our previous studies show that alterations in the Ink4a locus occur in only 15 and 27% of the lung and liver tumors, respectively. Preliminary data also suggests that the type of mutation induced in the Ki-ras gene fol lowing the initial exposure to MC may influence lung tumor progression. The se results imply that damage to the Ink4a gene is not a frequent pathway to malignant progression in mouse lung and liver tumors following in utero ex posure to environmental carcinogens. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.