**2.3 Adenomatous polyposis coli gene (APC)**

For carcinogenesis to develop, the Adenomatous Polyposis Coli gene (APC) mutation has to occur before the KRAS mutation. Therefore, the adenoma would not progress to carcinoma if one of the previous mutations happened without the other. APC, KRAS, and P53 are considered the CC driver genes (**Figure 2**). APC and KRAS mutated as an early event in the transition from normal epithelium to adenoma. However, after mutations or epigenetic silencing, the loss of P53 function can happen as late events. Moreover, P53 mutation makes cancer cells able to invade surrounding tissues and metastasize. As a result, SMAD4 and P53 loss of functions aid for the transformation of adenoma into a carcinoma (**Figures 2** and **3**) [16, 17].

Moreover, the APC gene is the gatekeeper gene for CC. The APC mutation is considered a frameshift mutation that causes truncation of the APC protein. The APC mutation hinders it from binding β-catenin to the membrane E-cadherin complex's cytoplasmic domain. As a result, cellular damage occurs [10, 16]. The free cytoplasmic β-catenin molecules, on the other hand, migrate to the nucleus to elicit the Wnt signaling pathway and cancer cell survival. Moreover, TGF-β and β-catenin are indeed cancer resistance indicators [16, 18].

TASIN-1 (Truncated APC Selective INhibitor) is a small chemical that has just been discovered to preferentially destroy cancer cells having APC truncations. TASIN-1 can reduce tumor development of APC shortened CC cells with low toxicity in both xenograft models and a genetically modified CC animal model [19].

**Figure 2.** *Driver genes mutations of CC and the histopathological impacts [10].* *DOI: http://dx.doi.org/10.5772/intechopen.105982 Colorectal Cancer Stages, Progress, Genetic Predisposition, and Immune Surveillance*

**Figure 3.**

*Stages for CC development and the driver genetic mutation [15].*

One of the most common events leading to CC transformation, as well as its aggressive and metastatic properties, is P53 tumor suppressor gene dysregulation. P53 reactivator mutant (PRIMA-1MET) has been studied in Phase I/II clinical trials and has shown promising results [15, 20].

### **2.4 B-cell lymphoma (BCL-2) and BCL-2-associated X protein genes (BAX)**

Mutations in genes controlling cell cycle checkpoint proteins (i.e. P53, BCL-2, and BAX) are the genetic drivers of CC and several types of cancers. The low level of BCL-2 expression and high level of BAX expression are correlated for better CC survival and control of cancer. The low BCL-2/BAX expression ratio leads to Cytochrome c (Cyto c) activation after external or internal stimuli. Cyto c is responsible for the Caspase family activation to trigger different cancer cells' apoptosis and phagocytosis (**Figure 4**). On the other hand, BCL-2 protein inhibits the action of the BAX protein that triggers the cancer cells' growth [21–23].
