A systematic effort is being made by Cellular and Molecular Pathology Branch scientists in collaboration with NTP/NIEHS scientists to identify genetic alterations in oncogenes and tumor suppresser genes and major genes which may play a role in cancer by genome wide analysis and other genetic methods in the most frequent sites for spontaneous and chemical-induced neoplasms in B6C3F1 mice and NTP rat models. The goal is to increase our understanding of the significance of increased incidence of neoplasms that are found following exposure of our standard rodent models to environmental chemicals. Knowledge of the spectrum of genetic alterations or genomic alterations that are present in chemically induced rodent tumors, their temporal appearance in the progression from preneoplastic lesions to neoplasms, and the way in which these factors may differ from tissue-to-tissue and chemical-to-chemical, will provide a molecular basis for distinguishing between spontaneous and chemically induced neoplasms. The approach is accomplished primarily from in-house collaborations. DNA and RNA are isolated from neoplasms in control and chemically treated rodents from prospective and retrospective studies and analyzed for genetic alterations using PCR based assays and genomic analysis. Retrospective studies to identify specific genetic alterations in neoplasms from previous bioassays involve examination of archival material primarily through PCR-based assays or genome wide analysis. These studies are being designed to correlate chemical-specific properties (structural features/genotoxicity/metabolism) with characteristics of the spectrum of genetic alterations present in preneoplastic and neoplastic lesions of specific target organs. This provides an opportunity to compare classes of chemicals, to evaluate structure/activity relationships within a class, and to evaluate the response of specific target tissues to different chemicals, without having to repeat the long-term studies. More importantly the data generated from NTP studies provide a molecular understanding of cancer and its relevance to humans.

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