We have explored transcriptional patterns associated with spontaneous cancer development and chemically-induced carcinogenesis. Gene expression patterns from spontaneous tumors arising in untreated B6C3F1 mouse lungs were compared with samples from lung in untreated age-matched control animals. Several canonical pathways associated with cancer were altered in the spontaneous tumors (e.g., RhoA and PTEN signaling), as well as pathways associated with metabolism (e.g., purine and pyramidine metabolism) and immune response (e.g., interleukin 8 and CXCR4 signaling). Meta-analysis of mouse tumors with human non-small lung cancer gene expression data sets were highly concordant. In another study, we also showed that exposure of B6C3F1 mice to Ginkgo biloba leaf extract involved altered transcriptional patterns associated with oncogenesis, hepatoceulluar carcinoma development and chronic xenobiotic and oxidative stress compared to spontaneous hepatocellular carcinoma. Comparing molecular pathways altered in spontaneous tumorigenesis versus those in chemically-induced tumors permitted us to explore the molecular underpinnings of these two different types of cancer progression in the context of normal subjects. In both studies, it was necessary to control mixed directional false discovery rate due to the fact that we tested for multiple comparisons and there is a potential for directional errors when declaring genes to be up- or downregulated. We are currently evaluating an approach to minimize sample size in toxicogenomics experiments using order-restricted inference and mixed-directional false discovery rate criteria.
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