What are the pathways to colon and rectal cancer?

Updated: Apr 06, 2021
  • Author: Burt Cagir, MD, FACS; Chief Editor: N Joseph Espat, MD, MS, FACS  more...
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Three pathways to colon and rectal carcinoma have been described:

  • Adenomatous polyposis coli ( APC) gene adenoma-carcinoma pathway
  • Hereditary nonpolyposis colorectal cancer (HNPCC) pathway
  • Ulcerative colitis dysplasia

The APC adenoma carcinoma pathway involves several genetic mutations, starting with inactivation of the APC gene, which allows unchecked cellular replication at the crypt surface. With the increase in cell division, further mutations occur, resulting in activation of the K-ras oncogene in the early stages and p53 mutations in later stages. These cumulative losses in tumor suppressor gene function prevent apoptosis and prolong the cell's lifespan indefinitely. If the APC mutation is inherited, it will result in familial adenomatous polyposis syndrome.

Histologically, adenomas are classified in three groups: tubular, tubulovillous, and villous adenomas. K-ras mutations and microsatellite instability have been identified in hyperplastic polyps. Therefore, hyperplastic polyps may also have malignant potential in varying degrees. [8]

The other common carcinogenic pathway involves mutation in DNA mismatch repair genes. Many of these mismatched repair genes have been identified, including hMLH1, hMSH2, hPMS1, hPMS2, and hMSH6. Mutation in mismatched repair genes negatively affects the DNA repair. This replication error is found in approximately 90% of HNPCC and 15% of sporadic colon and rectal cancers. [3, 9] A separate carcinogenic pathway is also described in inflammatory bowel disease (IBD). Chronic inflammation such as in ulcerative colitis can result in genetic alterations which then lead into dysplasia and carcinoma formation. [3]

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