A genetic basis for the multi-step pathway of colorectal tumorigenesis.

Colorectal tumors provide an excellent system in which to search for and study the genetic alterations involved in the development of a common human cancer. Data from many clinical and histopathological studies suggest that most carcinomas arise from preexisting adenomas. In addition, colorectal tumors of various stages of development can be obtained for studies of genetic alterations, unlike the situation in many other common human cancers in which only the most advanced lesions can be studied. A current view is that colorectal tumor development and progression results from the accumulation of somatic genetic alterations (mutations) in both oncogenes and tumor suppressor genes. Mutations in four to five genes may be necessary for the development of a malignant tumor; fewer changes may suffice for benign tumor formation. Although the genetic alterations often occur in a preferred sequence, the total accumulation of changes, rather than their order with respect to one another, appears to be a critical determinant of the biological properties of the tumor. Study of the genes targeted by somatic mutation in these tumors may provide insights, not only into the pathogenesis of the disease, but also into the mechanisms of origin of mutations and the potential environmental and dietary factors underlying colorectal tumor development.