Colorectal cancer (CRC) is one of the most common causes of death, despite decades of research. Initially considered as a disease due to genetic mutations, it is now viewed as a complex malignancy because of the involvement of epigenetic abnormalities. A functional equivalence between genetic and epigenetic mechanisms has been suggested in CRC initiation and progression. A hallmark of CRC is its pathogenetic heterogeneity attained through at least three distinct pathways: a traditional (adenoma-carcinoma sequence), an alternative, and more recently the so-called serrated pathway. While the alternative pathway is more heterogeneous and less characterized, the traditional and serrated pathways appear to be more homogeneous and clearly distinct. One unsolved question in colon cancer biology concerns the cells of origin and from which crypt compartment the different pathways originate. Based on molecular and pathological evidences, we propose that the traditional and serrated pathways originate from different crypt compartments explaining their genetic/epigenetic and clinicopathological differences. In this paper, we will discuss the current knowledge of CRC pathogenesis and, specifically, summarize the role of genetic/epigenetic changes in the origin and progression of the multiple CRC pathways. Elucidation of the link between the molecular and clinico-pathological aspects of CRC would improve our understanding of its etiology and impact both prevention and treatment. 1. Background: The Molecular Basis of Colon Carcinogenesis Colorectal cancers (CRCs) arise through a multistep process in which genetic and epigenetic alterations accumulate in a sequential order. Three different pathogenetic pathways have been implicated in the development of these tumors: (1) chromosomal instability (CIN); (2) microsatellite instability (MSI); (3) CpG island methylator phenotype (CIMP). The CIN pathway is associated with the sequential deregulation of tumor suppressor genes (TSGs) and oncogenes such as, APC, KRAS, DCC/SMAD4, and TP53. It generally occurs within inherited tumors, such as familial adenomatous polyposis (FAP), but it has also been associated with the majority of sporadic CRCs. Microsatellite instability is responsible for the Lynch syndrome and sporadic tumors and is mainly caused by inactivation of the DNA mismatch repair genes (hMLH1, hMSH2, hMSH6, and hPMS2). CRCs displaying MSI tend to be rightsided, generally have high histological grades, a mucinous phenotype, and diagnosed at lower pathological stages than CIN cancers. The CpG island methylator
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