Colorectal cancer is the third most common malignancy diagnosed in the human population. At least 861,000 deaths and 1.8 million new incidences were reported in 2018 (GLOBOCAN 2018). Colorectal cancer affects men more than women, and it is 3–4 times fold in developed compared to developing countries (Rawla et al., 2019). In the United States, colorectal cancer appears as number three in the scale of the most lethal cancers. Furthermore, from 1995-2016 the incidence of colorectal cancer in American men and women below the age of 50 gradually rose at a rate of 2% (Siegel et al., 2020). Colorectal cancer affects the rectum and colon parts of the large intestine and begins from the glandular epithelial cells when some of these cells develop a series of genetic mutations (Rawla et al., 2019). Following mutation, the cell begins to multiply abnormally and increase in number giving rise to a benign adenoma, which may gradually progress into carcinoma and spread to other body tissues. Understanding the different types of mutations arising from the glandular epithelial cells of the colorectal area is the first step toward generating targeted molecular therapies. This will help alleviate the health burden caused by these malignancies.

The Cancer Genome Atlas (TCGA) offers a comprehensive understanding of the molecular basis of cancers. TCGA colonic adenocarcinoma, (TCGA-COAD) and TCGA rectal adenocarcinoma (TCGA-READ) provide molecular knowledge of colorectal cancer. The project used 276 samples and investigated exome patterns, DNA duplicate number, promoter methylation, and the expression of mRNA and microRNA (Cancer Genome Atlas Network (2012). Two hundred two colon samples and 75 rectum samples were analyzed. The age average of the individuals whose samples were         analyzed in TCGA-COAD was 66.9, while TCGA-READ was 64.5 (Wang et al., 2018). In terms of race, TCGA-COAD had 215 whites, 59 blacks, and 11 from other ethnicities. TCGA-READ had 82 whites, six blacks, and one under other categories. There were slightly more males than females in both COAD and READ. The project identified more than 94% mutations in one or several members of the WNT signaling pathway.

Krüppel-like factor 5 (KLF5): plays an important function in controlling the growth of typical intestinal epithelial cells as well as colorectal cancer cells. A gene sequencing analysis of colorectal cancer tissues has led to the discovery of a somatic mutation (P301S) in KLF5 (Bialkowska et al., 2014). The mutation in the zinc finger transcription factor makes it difficult for the FBW7α to degrade it (Bialkowska et al., 2014). As such, the growth of intestinal epithelial cells continues unregulated.

Ets2 gene: This gene has been identified as significant in the Wnt signaling pathway associated with the development of colorectal cancer. The expression of Ets2 occurs within intestinal crypts. The T-cell factor (TCF) binding sites in the Ets2 promoter reveal a direct involvement in Wnt pathway whereas indirectly association is revealed in its regulation by the Achaete Scute-Like 2 transcription factor (Ascl2), which is a direct Wnt target in intestinal stem cells (Munera at al., 2011). The lack of Ets2 leads to elevated growth at the base of colon crypts.

SMAD2: This gene plays an important role in the transforming growth factor, TGF-β signaling pathway, which provides proliferation inhibitory signals in the typical intestinal epithelial cells (Jung et al., 2017). Mutations in SMAD2 hinder the formation of SMAD2- SMAD4 complex, which is critical in the inhibitory process. Therefore, mutations in SMAD2 block the tumor suppressor ability leading to colorectal cancer.

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Bialkowska, A. B., Liu, Y., Nandan, M. O., & Yang, V. W. (2014). A colon cancer-derived mutant of Krüppel-like factor 5 (KLF5) is resistant to degradation by glycogen synthase kinase 3β (GSK3β) and the E3 ubiquitin ligase F-box and WD repeat domain-containing 7α (FBW7α). The Journal of biological chemistry, 289(9), 5997–6005. https://doi.org/10.1074/jbc.M113.508549

Cancer Genome Atlas Network (2012). Comprehensive molecular characterization of human colon and rectal cancer. Nature, 487(7407), 330–337. https://doi.org/10.1038/nature11252

Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. https://gco.iarc.fr/

Jung B., Jonas J. S., and Beauchamp D. (2017). Transforming Growth Factor β Superfamily Signalingin Development of Colorectal Cancer. Gastroenterology 2017;152:36–52 https://www.gastrojournal.org/article/S0016-5085(16)35239-8/pdf

Múnera, J., Ceceña, G., Jedlicka, P., Wankell, M., & Oshima, R. G. (2011). Ets2 regulates colonic stem cells and sensitivity to tumorigenesis. Stem cells (Dayton, Ohio), 29(3), 430–439. https://doi.org/10.1002/stem.599

Rawla, P., Sunkara, T., & Barsouk, A. (2019). Epidemiology of colorectal cancer: incidence, mortality, survival, and risk factors. Przeglad gastroenterologiczny, 14(2), 89–103. https://doi.org/10.5114/pg.2018.81072

Siegel RL, Miller KD, Goding Sauer A, Fedewa SA, Butterly LF et al. (2020). Anderson JC, Cercek A, Smith RA, Jemal A. Colorectal cancer statistics, 2020. Cancer J Clin.

Wang, X., Steensma, J.T., Bailey, M. et al. (2018). Characteristics of The Cancer Genome Atlas cases relative to U.S. general population cancer cases. Br J Cancer 119, 885–892 https://doi.org/10.1038/s41416-018-0140-8