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

*Multidisciplinary Approach for Colorectal Cancer*

**2.1 Chromosomal instability**

genes [13, 14].

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].

The most frequent model of phenotype group in colorectal cancer are allelic losses in the short arm of chromosome 17 and 8 and in the long arm of chromosomes 5, 18 and 22, being approximately 80% of the sporadic form and are related to mutations in tumor suppressor genes of TP53 genes, APC, SMAD2, and SMAD4. The first major accepted model for cancer development in colon was described

The proto-oncogene K-ras (Kirsten-ras) tumor suppressor genes, APC protein (adenomatous polyposis coli), DCC protein (deleted in colorectal cancer) and TP53; and DNA repair or mismatch repair genes (MSH2, MLH1, PMS1, PMS2 and MSH6) are fundamental in development of CCR. Repetitive nucleotide sequences form approximately 25–40% of the DNA molecule being observed several times across the genome as dispersed replicates and tandem or satellite replicates [15]. These replicates can be classified according to the extension of the repetitive sequence in: satellite, minisatellite and microsatellite, depending on the number of nucleotides [16]. Most of the cases of CCR originate from polyps, but it was evidenced that about 45% of the tumors located in the proximal colon originated from epithelium without preexisting polyps, being considered new cancer [17]. In this model of carcinogenesis, which affects 10–15% of cases of sporadic CCR, instead of chromosomal instability there would be genomic instability due to mutations of DNA repair proteins, a phenomenon known as microsatellite instability (IMS) [18]. This pathway of colorectal carcinogenesis due to chromosomal instability is more frequently observed in tumors in the proximal colon, presenting characteristic histological features, being diploid, exophytic growth, worse histological grade, greater tendency to mucus production and lower mutation index in the TP53 gene,

by Fearon and Vogelstein in 1990. The majority of the sporadic CCR tumors originates from premalignant precursor lesions known as polyps, which over time progress to clinically relevant tumors. In this model, the sequence of events leading from the adenoma (polyps) to carcinoma was based on mutation on APC and TP53

and paradoxically, they are associated with a better prognosis [18, 19].

DNA is a molecule that often undergoes changes through loss of segments, mutations that occur during the process of cell division. To correct these changes, it has proteins with the function of performing the repairs necessary to maintain its integrity. These proteins are produced from some genes known as repair (mismatch

**30**

**2.2 Microsatellite instability**

repair genes—MMR) and this function is carried out continuously, preserving the cellular tissues [20–22]. The hMLH1 gene is located on chromosome 3p21-23 [23, 24], hMSH2 on chromosome 2p21 [25–27] and hMSH6 is on 2p16 [28].

In hereditary CCR there are two genetic pathways of carcinogenesis: a chromosomal instability pathway, which occurs in PAF (familial adenomatous polyposis), where the patient inherits a mutation of the APC (adenomatous colonic polyposis) tumor suppressor gene, and DNA hypermutability pathway, which occurs in HNPCC (inherited non-polyposis colorectal cancer) in which the inherited genetic change is the inactivation of one of the alleles of genes involved in DNA repair (hMSH2 and hMLH1 genes). However, other genes are involved in colorectal carcinogenesis, such as K-ras gene, DCC gene, Tp53 gene, etc. [29].

DNA is a molecule that often undergoes changes through loss of segments, mutations that occur during the process of cell division. To correct these changes, it has proteins with the function of performing the repairs necessary to maintain its integrity. These proteins are produced from some genes known as repair (mismatch repair genes—MMR) and this function is carried out continuously, preserving the cellular tissues [20–22]. The hMLH1 gene is located on chromosome 3p21-23 [23, 24], hMSH2 on chromosome 2p21 [25–27] and hMSH6 is on 2p16 [28].

MMRs have the function of recognizing the occurrence of the mutation and blocking cell division in order to prevent the emergence of a defective cell line, which is done by inducing cell death (apoptosis) or performing DNA repair. For the latter, these proteins remove a segment of DNA containing the change and insert a new segment containing the right sequence, based on the "template" of the complementary DNA [30].

The failure of these proteins to function will cause a great instability in the genome, that is, defects in the sequence of base pairs occurring at random in DNA replication cannot be adequately repaired, generating an accumulation of genetic abnormalities that favor the emergence of cancer [30].

A genetic instability that appears in 12–15% of CCR cases, named MSI (microsatellite instability) as a result of a mismatch repair (MMR), what leading to the accumulation of mutations in genes controlling cell cycle and apoptosis (TGFBRII, BAX or CASPASE5) [31].

Cells with changes in MMRs are not able to correctly repair errors during DNA replication. Because of their repetitive structure, microsatellite regions in DNA are particularly prone to these repair errors [32, 33]. The DNA of cells of certain tumors presents differences in the number of repetitive units in one or more microsatellites, when compared to the same microsatellites in the DNA of normal cells, a fact called microsatellite instability (MSI). as positive for replication errors, that is, RER (+) [34].

More than 90% of HNPCC patients present RER (+), while about 15% of sporadic CCRs present this genetic trait [30].

Repair proteins in their normal state form heterodimers [35–38]. MSH2 dimerizes with MSH6 forming the MutSα [38] functional complex, and MLH1 dimerizes with PMS2 to form MutLα [37, 39]. It has been shown that MSH2 and MLH1 proteins are obligatory parts of their respective heterodimers [40–42]. Their abnormalities may result in a proteolytic degradation of their dimers and consequently loss of both mandatory and secondarily associated proteins, the exception includes only MLH1 mutations, when the mutations result in the antigenically activation of the mutated MLH1 protein, which may be the loss of PMS2 only. The reverse, however, is not true, when mutation occurs in the genes of secondary proteins, for example, in MSH6 and PMS2, loss of MSH2 and MLH1 proteins that may not occur, inasmuch as other proteins compensate the function of the secondary proteins, such as MSH3, MLH3 and PMS1. In effect, mutations of MLH1 or MSH2 routinely cause loss of MLH1/PMS2 or MSH2/MHS6, respectively, while mutations of PMS2 or MSH6 cause isolated loss of PMS2 or MSH2 only [43].

**Figure 4** shows the model of DNA repair proteins in patients with colorectal cancer [44].

Studies performed in CCR demonstrated a positivity index for greater microsatellite instability in young patients or located in proximal segments of the colon. A study restricted to rectum tumors, the incidence of repair errors was only in 2% of cases, confirming the relationship between microsatellite instability and tumors located in the right or transverse colon [45]. The CCR associated with repair errors tend to present the same location and biological behavior independent of their sporadic or hereditary nature (HNPCC) [45].
