The

most common genetic mutation in colorectal cancer inactivates the gene that encodes the adenomatous polyposis coli (APC) protein. APC acts as part of the β-catenin degradation complex that controls levels of β-catenin through proteolysis. When the APC gene on chromosome 5q is mutated, there is a loss of functional APC protein which allows for the inappropriate and constitutive activation of the β-catenin -Wnt signaling pathway, which is regarded as the initiating event in colorectal cancer (20). Aberrant DNA methylation is an epigenetic mechanism of gene inactivation leading to genomic instability and associated carcinogenesis. 5-methylcytosine is a fifth Inhibitors,research,lifescience,medical DNA base that is introduced by DNA methylases within CpG islands of dinucleotides (20). In the normal genome, this occurs in non-coding Inhibitors,research,lifescience,medical regions of DNA and serves to “silence” un-needed portions of the genome. In the colorectal-cancer genome there is moderate depletion of overall cytosine methylation, but an increased amount of aberrant methylation within certain promoter-associated CpG islands. This can lead to aberrant promoter-associated methylation, which in turn induces epigenetic silencing of gene expression.

A subgroup of loci that becomes aberrantly methylated is known as the CpG island methylator phenotype (CIMP) that is seen in about 15% of colorectal cancers and all tumors with aberrant methlyation of mutL homolog 1 (MLH1) Inhibitors,research,lifescience,medical (20). A third form of genomic instability occurs through defects in DNA-repair mechanisms. These defects lead to inactivation Inhibitors,research,lifescience,medical of genes required for repair of base-base mismatches in DNA, a group known as mismatch-repair genes. This inactivation can be inherited, as in hereditary non-polyposis

colon cancer (HNPCC) or acquired, as seen in tumors with previously mentioned methylation-associated silencing of a gene encoding a DNA mismatch repair Inhibitors,research,lifescience,medical protein (20). The loss of mismatch-repair function is most easily recognized by the presence of microsatellite instability. This phenomenon leads to the inability to repair strand slippage within repetitive DNA sequences and leads to changes in the size of mononucleotide or dinucleotide repeats (microsatellites) scattered throughout the genome. The most commonly seen genes mutated are MLH1, mutS homolog 2 (MSH2), Nutlin3 postmeiotic segregation increased over 2 (PMS2) and mutS homolog 6 (MSH6) (20,21). Microsatellite instability, colon cancer, and lymph nodes A number of studies have shown differences in the pathologic features, survival, and even number of lymph nodes retrieved based on the degree of microsatellite instability observed (20-24). Of note, colorectal carcinomas with high-frequency microsatellite instability (MSI-H), as defined by more than 30% of microsatellite loci showing instability, tend to have a less aggressive course than microsatellite stable (MSS) tumors and tumors with low-frequency microsatellite instability (21-23).