*A Genetic Perspective on Colorectal Cancer Progression DOI: http://dx.doi.org/10.5772/intechopen.85894*

underlining of varying degrees of malignancy, each carrying a set of mutations. In this context, cancer is a multifactorial disease with an important genetic component, and mutations are central to its etiology and progression [8] (**Figure 2**).

The classical CCR carcinogenesis model is based on the adenoma-carcinoma sequence in which tumor onset occurs from a sequential and progressive process. This involves the activation of oncogenesis (K-ras) and the inactivation of tumor suppressor genes (APC, DCC, p53) [10, 11]. This model of carcinogenesis, where there is chromosomal instability, is usually found in the distal segments of the colon and rectum [11]. The adenoma-carcinoma sequence was described for the first time by Hill et al. (**Figure 3**) [12].

### **Figure 1.**

*Multidisciplinary Approach for Colorectal Cancer*

mutations with distinct pathways of progression [2].

**2. Molecular basis of carcinogenesis in colorectal cancer**

somatic cell, which then divides and proceeds to develop cancer [9].

would result in thousands of mutations in the DNA of the genome [8].

Considering a frequency of 10-10 replication errors per DNA basis, cell division, and about 1015 cell divisions over the life span of an adult, only replication errors

Once initiated, a cancer progresses through additional accumulation of genetic damage through mutations in maintenance genes, which encode the DNA repairing cellular machinery. Changes in these genes produce mutations in increasing numbers, leading to failures in controlling cell proliferation and repairing DNA damage. In this way, the original clone of neoplastic cells functions as a reservoir of genetically unstable cells, known as cancer stem cells. These give rise to multiple

comes even in the advanced disease.

In 1882 W. Harrison Cripps associated in his work that multiple intestinal polyposis had hereditary nature and also potentially malignant nature. Subsequently in 1913 Aldred S. Warthin reported on 1600 cases of carcinoma treated at University of Michigan for 19 years, collecting detailed family histories of approximately 500 patients and mapping a predisposition to gastrointestinal and endometrial carcinogenesis of three generations. In 1950, Eldon J. Gardner at University of Utah conducted a long genetic study in patient families with multiple polyps and established a link between this event and a predisposition to carcinomatosis only in 1986 Herrera et al. described a case of a patient with polyposis and multiple carcinomatosis, with an amputation in a long arm of chromosome 5, suggesting a location of tumor suppressor gene. Subsequent studies in families with polyps have identified the 5q21 region as adenomatous polyposis coli or APC gene. Since then, we have identified numerous genetic defects and genetic expressions showing a diversity of

There have been significant advances in the last years and more than understanding the risk factors for CCR, recent progress in the field of molecular biology, has allowed us to identify the oncogenesis basis to the development of the disease. Then apply these knowledge in the research of new drugs that lead to better out-

In medical practice, patients with cancer present with great frequency, clinical evolution in a differentiated way in response to the treatment performed. As a result, there is a high margin of uncertainty as to the effectuation of the treatment performed, not infrequently counting initially favorable prognostic evaluations [3]. Cancer results from a long process of at least three phases: initiation, promotion and progression, which reflect accumulated genetic alterations, responsible for the transformation of normal cells into neoplastic cells. The mechanisms of transformation of a normal cell into neoplastic involve a number of genetic and molecular events that affect proliferation and differentiation. In the pathogenesis of neoplastic processes, two groups of genes are involved: proto-oncogenes, which stimulate cell growth and impede differentiation, and tumor suppressor genes, which promote differentiation and limit cell proliferation. The imbalance in the regulation of this system, through the activation of proto-oncogenes or loss of the function of tumor suppressor genes, can lead to the uncontrolled proliferation of cells and to the accumulation of successive genetic abnormalities characteristic of neoplastic cells [4–7]. The development of cancer (oncogenesis) results from mutations in one or more genes, responsible for the regulation of cell growth and programmed cell death called apoptosis (**Figure 1**) [8]. When cancer occurs as part of a hereditary cancer syndrome, the initial mutation causing the cancer is inherited through germ lineage. However, most cancers are sporadic because mutations occur in a single

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*Mechanism of oncogenesis. General scheme for mechanism of oncogenesis by proto-oncogene activation, loss of tumor suppressor gene expression, activation of anti-apoptotic genes or loss of pro-apoptotic gene expression. The effect of the genes that induce a process is shown as +, while the effect of the genes that suppress a process is shown as −. Modified from Thompson and Thompson [8].*

### **Figure 2.**

*Stages in the evolution of cancer. Increasing degrees of abnormalities are associated with sequential loss of tumor suppressor genes from various chromosomes and activation of proto-oncogenes, with or without a defect, concomitant in DNA repair. Modified from Thompson and Thompson [8].*

### **Figure 3.**

*The adenoma-carcinoma sequence. Postulated mechanism for progression from normal tissue to adenoma to carcinoma. n: normal gene; p: adenoma gene (recessive), so that cell pp: is adenoma-prone. A: environmental agent causing adenomas only in adenoma-prone cell. B: environmental agent causing adenomas to grow. C: agent causing adenomas to develop into carcinomas. Modified from Hill et al. [12].*

In the colorectal carcinogenesis, there are a complex interaction between environmental and lifestyle factors and multiple molecular pathways contributes to its occurrence. Three different molecular mechanisms are implicated in colorectal carcinogenesis: chromosomal instability (CIN), genetic instability (GIN) and the serrated pathway. However, although they differ at the beginning of the chain of events, their signaling pathway, implicated in the transformation of the normal epithelial colorectal cell to the neoplastic one, appear to be similar and converge to the clinical and pathological manifestation of the disease. These genetic mechanisms can be acquired after birth and the occurrence of cancer is called sporadic or they can be inherited from the genitors and in this case is called hereditary. In the recent past, only clinical and pathological manifestations were considered when proposing the optimal treatment. However, after the understanding of the patterns implicated in the carcinogenesis, the tumors could be classificated according to molecular standards and individual treatment schemes were developed [13].
