The specific objectives of this research are: 1) to determine if these thymic lymphomas contain deletions in various chromosomes and 2) to determine if tumor suppressor gene expression occurs in these tumors. For this purpose B6C3F1 mice with intact ecotropic proviral sequences that can be activated, and NIH Swiss mice with truncated proviral sequences that cannot be expressed were treated with ddC for 6 months at a contract laboratory. Tymic lymphomas caused by ddC treatment were evaluated for tumor suppressor gene p53 activation by immunohistochemistry, and chromosome deletions by allelotype analyses in the Laboratories of the Environmental Toxicology Program and the Environmental Carcinogenesis Program. Only 20% (23 of 115) of the ddC-induced lymphomas, mostly from the high dose male and female NIH Swiss mice and female B6C3F1 mice were positive for p53 protein. The p53 staining intensity was minimal, heterogeneously distributed through the tumor and present in the nuclei of all tissues positive for p53 protein. However, a few (2 of 23) lymphomas showed a higher intensity of p53 staining with homogeneous distribution. Since the p53 protein was observed only in 20% of ddC-induced lymphomas with mostly minimal expression, the p53 mutation unlikely to be a major step in the development of ddC-induced thymic lymphomas. Allelic losses throughout the genome were generally infrequent except for chromosomes 2, 4, 11 and 12. Allelic losses were observed at a frequency of 38, 31, 25 and 19% in chromosomes 12, 2, 4 and 11, respectively. Some of the regions with allelic losses were homologous human chromosome regions frequently deleted in different types of human tumors. Thus, ddC appears to cause multiple genetic changes.
