New concepts of molecular biology for colon carcinogenesis

The progressive accumulation of genetic changes in both oncogenes and tumor -suppressor genes parallels the clinical and histopathologic progression fr om normal colonic epithelium through benign adenomas to frank colon cancer. A similar progression is postulated in the transition of normal squamous e pithelium to metaplastic mucosa (Barrett's esophagus) and subsequently thro ugh dysplasia to adenocarcinoma of the esophagus. A common link between col orectal cancer and Barrett's esophagus or esophageal carcinoma might be exp lained by either genetic predisposition or common environmental risk factor s. The multistep nature of oncogenesis is most directly illustrated by mole cular experimental genetic studies which demonstrate that the progression f rom adenoma to colon carcinoma results from the accumulation of molecular g enetic alterations involving mainly 3 factors: activation of oncogenes; ina ctivation of tumor-suppressor genes; and abnormalities in genes involved in DNA mismatch repair. Changes in oncogenes encoding four distinct groups of proteins (peptide growth factors, protein kinases, signal transducting pro teins, and nuclear transcriptional regulatory proteins) can contribute to c olon carcinogenesis. In addition, various carcinogens may act at different stages of this model, affecting somatic mutations and resulting in addition al genetic alterations. Other promoters, including hormones, may enhance th e likelihood of these events through the stimulation of the rate of cell tu rnover. Diseased detoxification processes may also play a role in carcinoge nesis.