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Abstract Colorectal carcinoma ranks the third most common type of cancer and constitutes a major contributor to cancer morbidity and mortality globally. In Egypt, colorectal cancer is not uncommon; representing the 6th most frequent cancer among both sexes combined. It is a heterogeneous disease with diverse histological and biological features, clinical presentations, behavior and response to therapy. The molecular pathogenesis of CRC has been recently evolved and CRC is increasingly classified into specific phenotypes based on different carcinogenetic pathways. Most colorectal carcinomas arise through a conventional adenoma-carcinoma sequence. Along the adenoma-carcinoma sequence, colorectal tumorigenesis can progress through either chromosomal instability pathway with multiple alterations in chromosome number, chromosomal rearrangements, or gene amplifications or the microsatellite instability pathway. Microsatellite instability (MSI) is a hypermutable phenotype caused by defects in DNA mismatch repair due to the inactivation of one of the four mismatch repair genes: MSH2, MLH1, MSH6, and PMS2. MSI is equivalent to the loss of staining by immunohistochemistry (IHC) of one of the mismatch repair genes; most frequently MSH2 and MLH1, since both signify an abnormality in mismatch repair. It became apparent that a subset of early onset CRC is characterized by a large number of mutations at MS sequences; 3% of these are associated with Lynch syndrome and the / |