Cancer is felt to be the result of a series of genetic changes which lead to progressive disordering of the controls which normally limit cell growth or invasiveness. In colorectal cancer, these mutations include changes in the K-RAS oncogene, and loss of alleles on chromosome 5, 17, and 18, presumably involving the FAP, p53, and DCC genes, respectively. Although there is little understanding of the mechanisms by which these genes interact to cause colorectal cancer, some evidence suggests that tumor aggressiveness may be related to progressive accumulation of these mutations; however, there has not been enough clinical data accumulated to prove this assertion. Now, with the initiation of clinical trials of adjuvant therapy for colorectal cancer in the cooperative group setting, we have the opportunity to collect tissue from a large number of prospectively-identified patients who will be uniformly-treated, and in whom there will be excellent data collection and clinical follow-up. This will enable us not only to determine the incidence of these mutational changes, but also to correlate our findings with clinical parameters, as well as tumor phenotype. Specifically, we propose to study tumor tissue prospectively collected from patients enrolled on CALGB protocols for colorectal cancer adjuvant therapy (1) to determine the incidence of mutations in RAS, and chromosomes 5, 17, 18; (2) to correlate mutations with clinical findings such as stage, response to therapy, long-term survival, and occurrence of later metastatic disease; (3) to determine, the association of specific DNA changes with the phenotypic and biochemical markers as measured by other companion studies (abnormalities in p53, or alterations in expression of oncogenes, ECGF receptor, and laminin receptors). These studies will lead to a better understanding of the biology of colorectal cancer, and will help to determine the clinical utility of DNA-based tests for determining prognosis and selecting therapy.
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