Colorectal Tumors

ABSTRACT

• Colorectal tumors progress through a series of clinical and histopathologic stages ranging from single crypt lesions (aberrant crypt foci) through small benign tumors (adenomatous polyps) to malignant cancers (carcinomas). This progression is the result of a series of genetic changes that involve activation of oncogenes and inactivation of tumor suppressor genes.

• Several inherited predispositions to colorectal cancer have been described. The two best characterized and most pronounced are hereditary nonpolyposis colorectal cancer (HNPCC) and familial adenomatous polyposis (FAP). Patients with HNPCC inherit defective DNA mismatch repair genes (Hereditary Nonpolyposis Colorectal Cancer (HNPCC)). Although HNPCC and FAP are both associated with a marked predisposition to colorectal cancer, they account for only a small fraction of colorectal cancers. Most colorectal cancers occur in the absence of a recognized inherited factor and are considered sporadic.

• 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 ...