We have seen that the development of colorectal cancer frequently involves sequential gene mutations. Specific genes that regulate cellular adhesion, angiogenesis, cell signaling, growth factors, and apoptosis are thought to play a pivotal role. Tap each of the genes listed for more information on these important genes.
Inactivation of the APC gene is an early event in malignant transformation. The APC gene protein indirectly regulates the transcription of a number of critical cell proliferation genes, by interacting with the transcription factor, β-catenin. Normally, the APC protein facilitates the degradation of β-catenin, which plays an important role in cell-cell adhesion. β-catenin also interacts with the Wnt-signaling pathway that helps determine cell fate. The loss of an effective APC protein and the accumulation of excess β-catenin enhances cell proliferation and inhibits apoptosis.
KRAS is a member of the MAP kinase (MAPK) pathway. The RAS/RAF/MAPK pathway regulates cell proliferation, differentiation, senescence, and apoptosis. RAS oncogenes include HRAS, NRAS, and KRAS, with KRAS being the most commonly mutated. Approximately 40% of sporadic colorectal cancer cases are associated with a KRAS mutation. The MAPK pathway plays a major role in conducting cell proliferation signals from the cell surface to the nucleus. This pathway uses a series of intermediate proteins including RAS, RAF, and MEK. The binding of growth factors to epidermal growth factor receptors, or EGFRs, results in activation of the receptor and the MAPK pathway. KRAS mutations lead to changes in the KRAS protein that make it constitutively, or constantly active. This promotes cell proliferation and survival independent of the EGFR receptor. For this reason, therapeutic EGFR inhibition is ineffective, since KRAS is located downstream from EGFR.
BRAF is a member of the RAF family of kinases. Like KRAS, it mediates cellular responses to growth signals through the RAS-RAF-MAPK pathway. Activating mutations in BRAF V600E are found in up to 10% of sporadic colorectal cancer cases. Colorectal cancer patients with BRAF V600E mutations have a poorer prognosis than patients with wild-type BRAF. BRAF mutations are, for all practical purposes, limited to those tumors that do not have RAS (KRAS and NRAS) mutations, as BRAF is downstream of activated KRAS in the EGFR pathway.
The TP53 gene is involved in the control of the cell cycle and apoptosis and is commonly mutated in patients with colorectal cancer. The p53 protein induces G1 cell-cycle arrest and facilitates DNA repair prior to a cell committing to the process of DNA replication. If DNA repair is unsuccessful, p53 induces cell death through the process of apoptosis. TP53 mutations are generally believed to occur around the time a benign adenoma transitions to cancer. Numerous studies have attempted to elaborate on the prognostic significance of TP53 mutations in CRC, with conflicting results.
