Role of ornithine decarboxylase (ODC) as a oncogene in colorectal tumorigenesis

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Omithine decarboxylase, a critical regulatory enzyme for polyamine byosynthesis, is highly regulated in human colorectal cancer. Defects in mispatch repair function can lead to the microsateillite instability (MI) phenotype in certain human cancers. During our analysis of polyamine metabolism in colorectal cancinomas and its relationship to clinical parameters, we were struck by the similarity between published data of clorectalcancerpatients with MI phenotype and those patients in our series with high level of tumor ODC activity (especially a particular isoform of ODC which can be activated by GTP) : both sets of patients tend to have right sided tumors and good prognosis. We therefore examined the genetic alterations, such as mutations or the structural alterations, accounts for the tumor ODC.No mutations or structual alterations were detected in ODC genes from any of the colorectal tumor as well as normal tissue examined. These results suggest that mutation in coding sequence of ODC or structual alteration of the gene that might affect the charactristics of alterd ODC function may not be involved in human colorectal cancers.In the course of our study of ODC and MI pohenotype, we have identified E2F-4, important transcription fuctor in cell-cycle control, having frequent tumor-specific mutations at the trinucleotide coding microsatellite (CAG repeats) in a subset of human sporadic CRC with MI phenotype. We also found a relatively high rate of mutation within E2F-4 in gastric cancer and ulcerative colitis related tumor with MI.Additional investigations revealed that somatic mutation in E2F-4 gene are closely associtated with defects in the hMSH3 gene and are possibly selectedduring the progression of colorectal MI tumors.