Colorectal Cancer is a very heterogeneous disease, and except from some genetic mutations in tumor suppressing and tumor promoting genes (APC, p53, KRAS), the other genes involved are found in very low proportion of cases. Colorectal Cancers are mostly sporadic (⁓70%-80%) and increased with aging. Exceptions are some inherited forms including familial adenomatous polyposis (⁓1%), non-polyposis hereditary CRC or Lynch syndrome (2%-5%) or MYH-gene associated polyposis (< 1%). The hallmark feature that occurs among transmission of normal colonic epithilium to neoplastic includes genomic instability (GI), which is divided to a) chromosomal instability (CIN) and b) microsatellite instability (MSI) and epigenomic instability (EI).
The major genes that loss their function during CIN involve the basic tumor-suppressor genes such as adenomatous polyposis coli (APC), p53, SMAD4, and tumor-suppressor genes on chromosome 18q the area deleted in colon cancer (DCC), and the ones that gain function include the k-ras oncogene. MSI includes mutations in genes responsible for the repair of errors that occur during the replication of DNA, such as MLH1, MLH3, PMS1, PMS2, MSH2, MSH3, MSH6 as well as Exo1. Finally EI involves aberrant hypermethylation, a mechanism responsible for silencing gene expression. Two mechanisms of EI have been mostly described in CRC: Dinucleotide methylation in the promoter area of many genes, known as CpG island methylator phenotype (CIMP), and global DNA hypomethylation. A tumor is considered CIMP-positive if it is methylated in at least 3 of the following biomarkers: CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1.