What is the pathophysiology of colon cancer?

Pathophysiology of Colon Cancer

Colon cancer develops primarily through two major molecular pathways: chromosomal instability and microsatellite instability, with a third pathway involving epigenetic changes through DNA methylation, all of which drive the adenoma-carcinoma sequence that transforms normal colonic epithelium to invasive cancer over years to decades. 1

Adenoma-Carcinoma Sequence

The development of colon cancer follows a well-established progression from normal epithelium to adenomatous polyps to invasive carcinoma:

• Initial Events: Inactivation of the APC/beta-catenin pathway is typically the earliest event in colorectal carcinogenesis 1
• Intermediate Events: Followed by activation of proto-oncogenes such as K-ras and inactivation of tumor suppressor genes 1
• Late Events: Further progression involves inactivation of p53, DCC, and SMADs on chromosome 18q and other suppressor genes on chromosomes 8p and 1p 1

Major Molecular Pathways

1. Chromosomal Instability Pathway (70-85% of cases)

• Characterized by prominent allelic losses and gains reflecting extensive cytogenetic abnormalities 1
• Sequential genetic alterations include:
  • APC gene mutations (chromosome 5q) as the initiating event
  • K-ras proto-oncogene activation
  • Loss of tumor suppressor genes on chromosome 18q (DCC, SMAD4)
  • p53 inactivation on chromosome 17p (typically a late event)

2. Microsatellite Instability Pathway (15% of cases)

• Distinguished by extensive nucleotide insertions or deletions in microsatellite sequences 1
• Results from inactivation of DNA mismatch repair genes (hMSH2, hMLH1, hPMS2, or hMSH6)
• Genetic alterations accumulate in coding regions of numerous genes including:
  • Type II receptor for transforming growth factor beta
  • BAX proapoptotic gene
  • E2F-4 transcription factor gene
  • IGF gene

3. CpG Island Methylator Phenotype

• Involves hypermethylation of promoters of several genes including MLH1, p16, and other tumor suppressor genes 1
• Results in inhibition of gene expression and tumor progression
• May overlap with microsatellite instability when hMLH1 is methylated

Hereditary Syndromes

Familial Adenomatous Polyposis (FAP)

• Caused by germline mutations in the APC gene on chromosome 5q21-22 1
• Characterized by hundreds to thousands of adenomatous polyps in the colon and rectum
• Nearly 100% risk of developing colorectal cancer if left untreated
• Accounts for approximately 1% of all colorectal cancers

Hereditary Non-Polyposis Colorectal Cancer (HNPCC/Lynch Syndrome)

• Autosomal dominant syndrome caused by mutations in DNA mismatch repair genes 1
• Characterized by development of colorectal cancer without preceding multiple adenomas
• The DNA mismatch repair defect accelerates malignant transformation of sporadic adenomas 1
• Accounts for 2-3% of all colorectal cancers

Precursor Lesions

Two main types of precursor polyps have been identified:

1. Conventional Adenomas:

   • Arise from mutations in the APC gene
   • Progress through the conventional adenoma-carcinoma sequence

2. Serrated Adenomas:

   • Follow the serrated adenoma-carcinoma pathway
   • Often associated with BRAF mutations and CpG island methylator phenotype

Environmental and Lifestyle Factors

Several factors modify the risk of developing colorectal cancer:

• Protective Factors:

  • Regular use of non-steroidal anti-inflammatory drugs (40-50% reduction in risk) 1
  • Calcium supplementation (15% reduction in polyp recurrence) 1
  • Aspirin use (18-28% reduction in polyp recurrence) 1

• Risk Factors:

  • High-fat diet
  • Low fiber intake
  • Low fruit and vegetable consumption
  • Smoking

Clinical Implications

Understanding the pathophysiology of colon cancer has important clinical implications:

• Screening: Early detection of precancerous polyps allows for intervention before progression to cancer
• Risk Stratification: Molecular features can help predict prognosis and guide treatment decisions
• Targeted Prevention: Identification of high-risk individuals through genetic testing enables tailored surveillance
• Therapeutic Targets: Molecular pathways provide targets for novel therapeutic approaches

The molecular understanding of colon cancer pathophysiology continues to evolve, with ongoing research into additional genetic and epigenetic alterations that contribute to tumor initiation and progression.