The majority of mutations contributing to colorectal tumorigenesis are acquired in the tumor cell (i.e., somatic). Genetic alterations affecting genes functioning in the following five pathways are commonly observed: APC, RAS/RAF, TGF-β, AKT, and p53.
i. Mutations in the APC pathway initiate colorectal tumorigenesis. In addition to causing FAP through germ-line transmission, mutations of the APC gene occur somatically in more than 80 percent of sporadic colorectal tumors, whether benign or malignant. Almost all of these mutations, like the inherited mutations causing FAP, are predicted to result in truncation of the APC protein. At the biochemical level, one critical function of APC is inhibition of β-catenin/Tcf-mediated transcription. Mutation of APC leads to increased β-catenin/Tcf-mediated transcription of growth-promoting genes including the c-MYC oncogene. In the unusual tumors without APC mutations, increased β-catenin/Tcf-mediated transcription results from mutations of β-catenin that render it resistant to the inhibitory effects of APC.
ii. Activating mutations in genes of the RAS/RAF pathway occur in benign tumors and appear to drive their clonal expansion into larger tumors. The majority of these mutations affect the c-Ki-RAS gene with the rest affecting the N-RAS and BRAF genes. The RAS proteins are small G proteins that activate the BRAF kinase, which in turn phosphorylates proteins that stimulate cell growth.
iii. Inactivating mutations of tumor suppressor genes controlling the transforming growth factor β (TGF-β) pathway occur during the latter stages of benign tumorigenesis. Mutations of the type II TGF-β receptor occur in nearly all tumors that are mismatch repair deficient. In tumors that are mismatch repair proficient, inactivating mutations of the SMAD genes, particularly SMAD4, have similar effects. The SMAD proteins are activated by TGF-β receptors and transduce the negative growth controlling effects of this cytokine.
iv. Mutations in the AKT pathway occur near the transition from benign to malignant tumors, marked by the invasion of the latter through the underlying basement membrane. The most common mutations in this pathway are activating mutations of PIK3CA, a lipid kinase that phosphorylates phosphatidylinositol diphosphate. The phosphorylated lipid product of this reaction activates the AKT serine/threonine kinase, which in turn phosphorylates products important for stimulating cell division or inhibiting cell death. Inactivating mutations of PTEN, a lipid phosphatase that reverses the action of PIK3CA, or activating mutations of other genes in this pathway, are observed in some of the tumors that do not harbor PIK3CA mutations.
v. The p53 pathway is inactivated near the transition from benign to malignant tumors. This gene is inactivated in >85 percent of colorectal cancers, most commonly as a result of a missense mutation combined with loss of the wild-type allele. The p53 protein is a transcription factor that normally activates genes inhibiting cell birth or promoting cell death. Mutant p53 is defective in these activities.