**2.2 Microsatellite instability**

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

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

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],

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],

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

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

hMSH2 on chromosome 2p21 [25–27] and hMSH6 is on 2p16 [28].

carcinogenesis, such as K-ras gene, DCC gene, Tp53 gene, etc. [29].

hMSH2 on chromosome 2p21 [25–27] and hMSH6 is on 2p16 [28].

abnormalities that favor the emergence of cancer [30].

sporadic CCRs present this genetic trait [30].

MSH6 cause isolated loss of PMS2 or MSH2 only [43].

BAX or CASPASE5) [31].

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

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,

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

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
