Adenocarcinomas of the colon and rectum (colorectal cancer, CRC) are malignant epithelial neoplasms. A polyp is a localized lesion that projects above the surrounding mucosa. Adenomatous polyps (adenomas) are benign neoplasms that arise from colorectal glandular epithelium. In the United States (US), colorectal adenoma (CRA) prevalence is approximately 25% by age 50 and rises to around 50% by age 70. The histological hallmarks of a CRA are altered glandular architecture and dysplasia of the epithelium. The great majority of CRCs develop from CRAs in a process called the adenoma-carcinoma sequence. This process may take from years to decades for the earliest CRA to progress to CRC (Leslie et al. 2002). A CRA progresses to become a CRC when the dysplastic cells invade through the muscularis mucosa. While most CRCs develop from CRAs, fewer than 10% of CRAs ever progress to CRC. Hyperplastic colorectal polyps are histologically distinct from CRAs, occur most frequently in the rectum and sigmoid colon, are not neoplastic and do not progress to CRC. Besides CRAs, the inflammatory bowel diseases, ulcerative colitis (UC) and Crohn's disease of the colon (Crohn's colitis), predispose to CRC. CRCs evolve through distinct genetic pathways involving genetic instability, which is the driving force for tumor development (Lengauer et al. 1998). Three genetic instability pathways have been identified in CRC. They are called chromosomal instability (Rajagopalan et al. 2003), microsatellite instability (MSI), and the CpG island methylator phenotype (CIMP). Chromosomal instability is the tumorigenic mechanism in FAP and in approximately 85% of sporadic CRCs that develop as a result of losses of both APC alleles and other tumor suppressor genes (Vogelstein et al. 1988). HNPCC and the remaining 15% of sporadic CRCs develop because of MSI that results from inactivation of the DNA MMR system (Ionov et al. 1993). Clusters of cytosine-guanosine pairs, termed CpG islands, in the promoter regions of many genes are prone to age-related methylation. Such hypermethylation can lead to gene silencing. In a proportion of CRCs, functional loss of certain tumor suppressor genes is caused by CpG island methylation and silencing rather than mutations (Toyota et al. 1999).
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