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 (Chap. 32). 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 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.
Despite the requirement for multiple somatic mutations to drive the neoplastic process, several inherited predispositions can result from inheritance of a single defective gene as noted above. The genes responsible for cancer predispositions can be broadly grouped into three categories of defects: caretakers, gatekeepers, and landscapers. Examples of all three defects exist for colon cancer. Caretaker defects are typified by the DNA mismatch repair alterations observed in HNPCC. While these defects do not act directly to affect cellular growth, they act as caretakers reducing the accumulation of mutations that arise during the normal replication of DNA. Defects in DNA mismatch repair lead to a genetic instability that accelerates the progression of cancer. In contrast, patients with FAP inherit truncating mutations of the APC tumor suppressor gene. APC functions as a gatekeeper directly regulating the growth of colorectal epithelial cells. As a result of inheriting a mutant gatekeeper gene, patients with FAP develop hundreds of benign colorectal tumors, some of which progress to carcinomas. The third category of predispositions results from landscaper defects. Landscaper defects do not directly affect cancer cell growth but contribute to abnormal stromal environment that contributes to the neoplastic transformation of the overlying epithelium. The increased risk of colorectal cancer observed in Peutz-Jeghers syndrome may be the result of landscaper defects.
The analysis of mutations in colorectal tumors at various stages of their development allows definition of a model for colorectal tumor development. Mutations in the APC gene appear to initiate this process, resulting in small tumors representing the clonal growth of a single cell. One of the cells in this small tumor may acquire an additional mutation (often in the K-RAS or BRAF genes), allowing it to overgrow surrounding cells and resulting in a larger tumor. Subsequent waves of clonal expansion are driven by sequential mutations in the the genes controlling the other three pathways described above. Along with this expansion comes further cellular disorganization and eventually the ability to invade and metastasize. While this accumulation of multiple genetic changes is driven by growth advantages, it can also be facilitated by an innate genetic instability (Chap. 22). In a small but significant fraction of cancers, this genetic instability is due to a defect in DNA mismatch repair. In the majority of cancers, accumulation of genetic changes is the result of chromosomal instability.