As discussed earlier, Lynch syndrome results from loss of function in one of the MMR genes and follows the MSI neverless pathway (“mutator” pathway).

In contrast, FAP arises in patient with inherited mutations in the APC gene, which has been the center of the original Fearon-Vogelstein model of colorectal tumorigenesis (97) that forms the basis of chromosomal instability (CIN) pathway (“suppressor” pathway). Both MSI and CIN pathways describe colorectal cancer pathogenesis based on genetic abnormities that lead to loss of function of tumor suppressor genes and/or gain of function of oncogenes. In the last decade, epigenetic instability Inhibitors,research,lifescience,medical has gained considerable attention and is now believed to be implicated in the pathogenesis of almost Inhibitors,research,lifescience,medical one third of colorectal cancers (49). In addition to DNA sequence and structure, gene expression is controlled by a number of epigenetic modifications that include DNA methylation, histone alterations and chromatin remodeling (98). One of the best characterized epigenetic modifications associated Inhibitors,research,lifescience,medical with colorectal tumorigenesis is silencing of genes (tumor suppressor

and/or MMR genes) through hypermethylation of their promoter regions. Although it was debated whether the phenomenon of epigenetic instability represents an adaptive cellular mechanism during carcinogenesis aimed to abort cellular proliferation, a secondary alteration to yet unidentified genetic mutations, a phenomenon expected to occur during tumor cell senescence, or simply an artifact (99-104), transcriptional silencing of certain Inhibitors,research,lifescience,medical genes by hypermethylation has undoubtedly shown to result in tumor development (105-110). In particular, promoter hypermethylation of the MLH1, one of the MMR genes, is demonstrated in the majority of sporadic colorectal cancers with a MSI phenotype (108,111,112). Inhibitors,research,lifescience,medical Since many genes are

rich in cytosine and guanine dinucleotides (CpG islands) in their promoters, methylation of the cytosine residues in CpG islands is a common phenomenon, which leads to alterations of the chromosomal structure and suppression of gene expression. Colorectal cancers with CpG island methylator phenotype (CIMP) are characterized by epigenetic loss of function of tumor suppressor genes without mutations (49,113). Figure 19 summaries the current understanding of the molecular pathways involved in colorectal tumorigenesis. CIN pathway is implicated in both sporadic and syndromic colorectal GSK-3 cancers. CIN tumors are characterized by karyotypic abnormalities and chromosomal gains and losses, which can be assessed by DNA ploidy or loss of heterozygosity (LOH) analyses. These tumors almost always harbor APC mutations, frequently show KRAS and p53 mutations, and often have 18q allelic loss (3,94). MSI pathway is also implicated in both sporadic and syndromic colorectal cancers and tends to be kinase inhibitor Bortezomib mutually exclusive with CIN.