Etiology

Excluding skin cancers, colorectal cancer is the fourth most common cancer in the US overall

third leading cause of cancer-related deaths in the US overall

Chromosomal instability pathway in colon cancer: The adenoma-carcinoma sequence is the progressive accumulation of mutations in oncogenes (e.g., KRAS) and tumor suppressor genes (e.g., APC, TP53) that results in the slow transformation of adenomas into carcinomas.

• APC gene mutation (loss of cellular adhesion and increased cellular proliferation) → KRAS gene mutation (unregulated cellular signaling and cellular proliferation) → TP53 and DCC gene mutation

• Most cases of sporadic CRC develop via this pathway.

Microsatellite instability pathway in colon cancer: due to methylation or mutations in mismatch repair genes (MMR genes, e.g., MLH1 or MSH2)

Hypermethylation phenotype pathway in colon cancer

• CpG island methylator phenotype (CIMP): global hypermethylation of CpG islands → silencing of MMR gene expression

• Associated with BRAF mutations

• Up to 20% of sporadic CRCs develop from serrated polyps that underwent malignant transformation via this pathway.

COX-2 overexpression

• Associated with colorectal cancer

• Possible protective effect of long-term use of aspirin and other NSAIDs

Age: older age (> 40 years)

Hereditary syndromes

• Family history: Approx. 25% of individuals with colorectal cancer (CRC) have a positive family history.

• Familial adenomatous polyposis: 100% of individuals will have developed CRC by the age of 40 years, Gardner syndrome, Turcot syndrome, Peutz-Jeghers syndrome, Juvenile polyposis syndrome)

• Hereditary nonpolyposis colorectal cancer (HNPCC): progression to CRC in 80% of cases

Associated conditions

• Colorectal adenomas and serrated polyps

• Inflammatory bowel disease: chronic inflammation → hyperplasia → non-polypoid dysplasia → neoplasia

  • Ulcerative colitis

  • Crohn disease

• Endocarditis and bacteremia due to S. gallolyticus

• Diabetes mellitus type 2

Lifestyle

• Smoking

• Alcohol consumption

Diet

• Obesity

• Processed meat

• High-fat and low-fiber

Other: History of abdominal radiation during childhood

Long-term use of aspirin and other NSAIDs

Physical activity

Diet rich in fiber and vegetables and lower in meat