SPECIFIC PATTERNS OF ONCOGENE ACTIVATION IN TRANSPLACENTALLY INDUCED-TUMORS

Transplacental exposure of rats to a single dose of the direct acting carcinogen methylnitrosourea (MNU) results in the induction of a variety of neoplasias of neuroectodermal, epithelial, and mesenchymal origin. Molecular analysis of the oncogenes present in these tumors revealed a strinking degree of tissue specificity. neu oncogenes were found to be reproducibly activated in tumors derived from the peripheral nervous system (PNS), but not in those arising from the central nervous system (CNS). No ras oncogenes were found in either PNS- or CNS-derived tumors. However, Ha-ras oncogenes were detected in each of three mammary carcinomas and Ki-ras oncogenes were present in each of five kidney mesenchymal tumors. These results illustrate that phenotypic expression of activated oncogenes in vivo is not a random process and suggest that abnormal developmental programs may play an important role in modulating the activation of specific oncogenes by chemical carcinogens. PCR analysis revealed that each of the ras oncogenes detected in these transplacentally induced tumors became activated by the same G → A transition in the second base of codon 12. Since G → A transitions are the preferred mutations induced by MNU, it is likely that these ras oncogenes may have been directly targeted by MNU during embryonic development.