Colon cancer is one of the most common malignancies in the United States, afflicting over 160,000 individuals per year. Recently, adjuvant chemotherapy, given alone for colon cancer or combined with radiation therapy for rectal cancer, has been demonstrated to be of clinical utility. Although standard clinical, surgical, and pathologic staging are available, additional prognostic markers are still critically needed to more precisely define the subsets of patients who would benefit most from such therapy. Such prognostic markers may come from our increasing understanding of the underlying molecular basis of tumor formation in colorectal cancer. Genetic alterations currently described in colorectal cancer include the activation of oncogenes and the inactivation of tumor suppressor genes. However, more recent unpublished data from our laboratory suggests the presence of a novel genetic mechanism of tumorigenesis which, unlike those previously described, results in genetic instability of certain chromosomal elements. Based on a variety of observations, tumors demonstrating this instability appear to be genetically distinct from the majority of sporadic tumors. These genetic alterations, as well as those previously described for oncogenes and. tumor suppressor genes, have the potential to provide additional, and perhaps even better prognostic discrimination than what is currently available. Therefore, it is the intent of this proposal to determine the clinical and pathologic significance of a variety of molecular genetic changes that occur in colorectal cancer. These include: a) the evaluation of unstable DNA elements; and b) loss of heterozygosity for chromosomes 5, 8, 17, and 18 as the primary targets and 1, 14, and 22 as the secondary targets. To accomplish these goals, paraffin embedded material from approximately 700 well-characterized patients, who have undergone surgery for colorectal cancer and who were followed prospectively on formal surgical adjuvant treatment protocols, will be examined. Both genomic instability and loss of heterozygosity will be assayed simultaneously with the use of PCR-based assays directed toward the identification microsattelites (also known as (CA)n repeats). For the initial studies, a minimum of 10 separate (CA)n repeats will be examined, two each for chromosomes 5, 8, 15, 17, and 18.
