The biology of colorectal cancer. Implications for pretreatment and follow-up management.

The biology of colorectal cancer is discussed in terms of multistage carcinogenesis. Colorectal cancer evolves through the stepwise acquisition of mutations at certain critical genetic loci, many of which have been identified recently. The earliest step in the neoplastic pathway is a shift of proliferation from the normally restricted zone at the base of the colonic crypt and the retention of cells capable of proliferation at the top of the colonic crypt. This appears to be mediated by a mutation in the APC gene. The adenoma, a collection of benign neoplastic cells, is the first pathologically recognizable neoplastic lesion. Adenomas may grow or involute. Additional genetic lesions, such as a mutation in the Ki-ras gene, contribute to the growth and progressive dysplasia of the adenoma. Critical lesions in the p53 gene appear to be responsible for malignant transformation and the appearance of genetic instability of the neoplastic cell, which greatly increases the likelihood that additional genetic events will occur that contribute to a progressively more aggressive neoplastic phenotype. Genetic and phenotypic diversity develop within the primary malignant tumor, and metastasis occurs as a consequence of a complex series of events. Opportunities for detection and therapeutic intervention in colorectal neoplasia are discussed in this framework.