A genetic model for colorectal tumorigenesis.

Tumorigenesis has long been thought to be a multistep process (Foulds, 1958); however, only recently has it become possible to identify the molecular events that underlie the initiation and progression of human tumors (Weinberg, 1989; Bishop, 1987). Colorectal tumors provide an excellent system in which to search for and study the genetic alterations involved in the development of a common human neoplasm. Abundant clinical and histopathological data suggest that most, if not all, malignant colorectal tumors (carcinomas) arise from preexisting benign tumors (adenomas) (Sugarbaker et al., 1985). Tumors of various stages of development, from very small adenomas to large metastatic carcinomas, can be obtained for study, unlike the situation in most other common human tumor types. Furthermore, both hereditary and environmental factors contribute to the development of colorectal neoplasia, allowing for the study of both inherited and somatic genetic alterations. In this review we present a model for the genetic basis of colorectal neoplasia that includes the following salient features. First, colorectal tumors appear to arise as a result of the mutational activation of oncogenes coupled with the mutational inactivation of tumor suppressor genes; the latter changes predominate. Second, mutations in at least four to five genes are required for the formation of a malignant tumor. Fewer changes suffice for benign tumorigenesis. Third, although the genetic alterations often occur according to a preferred sequence, the total accumulation of changes, rather than their order with respect to one another, is responsible for determining the tumor’s biologic properties. Fourth, in some cases, mutant tumor suppressor genes appear to exert a phenotypic effect even when present in the heterozygous state; thus, some tumor suppressor genes may not be “recessive” at the cellular level. The general features of this model may be applicable to other common epithelial neoplasms, in which tumors of varying stage are more difficult to study.