ACTIVATING POINT MUTATIONS OF THE NEU ONCOGENE IN SCHWANNOMAS INDUCED BY ETHYLNITROSOUREA EXPOSURE TO DAY-15 AND DAY-18 FETAL RATS

Abstract

Single transplacental exposure of day 15 fetal rats to the carcinogen ethylnitrosourea (ENU) primarily induces tumours of neuroectodermal origin, whereas exposure to ENU at neonatal and adult stages results in tumours arising predominantly from secretory epithelial tissue. Expression of the neu gene is found in fetal neural tissue up until day 16 of gestation, but predominantly only in secretory epithelium after this time. The presence of an activating mutation in the neu oncogene has been associated with these ENU induced neuroectodermal tumours, and on this basis it has been proposed that only the transcriptionally active neu gene is susceptible to ENU induced mutation. In this study we compare the spectrum of tumourigenesis in rats exposed to ENU on days 15 and 18 of gestation. Neuroectodermal rumours were produced at high incidence; mostly schwannomas derived from the peripheral nervous system and some gliomas of the central nervous system. PCR analysis of DNA from these tumours reveals that schwannomas predominantly (29/37=78%) contain a mutated neu gene. This consistent T-->A transversion at codon 671 is known to convert neu into a potent oncogene. Conversely gliomas and various carcinomas do not contain such a mutation (0/13=0%). Our data reveals little difference either in tumour type or activation of the neu oncogene in rats exposed to ENU at these two stages of development. However, we do find that the c-neu gene is expressed at both days 15 and 18 in fetal rat neural tissue; albeit at lower levels by day 18.