What is the etiology of early-onset colorectal (colon) cancer?

From the Guidelines

The etiology of early onset colon cancer is multifactorial, involving both genetic and environmental factors, with hereditary syndromes accounting for approximately 20% of cases, and the most recent evidence suggests that initiating screening colonoscopy at age 45 years instead of 50 years is the most optimal balance of burden to benefit of screening 1.

Key Factors Contributing to Early Onset Colon Cancer

• Hereditary syndromes, such as Lynch syndrome and familial adenomatous polyposis, are the most common genetic causes, with other genetic factors including mutations in genes like APC, MLH1, MSH2, MSH6, PMS2, and MUTYH 1
• Environmental and lifestyle factors, particularly the Western diet high in processed meats and low in fiber, obesity, physical inactivity, smoking, and alcohol consumption, play a significant role 1
• Emerging research suggests that gut microbiome dysbiosis, with decreased beneficial bacteria and increased pathogenic species, contributes to inflammation and carcinogenesis 1
• Early life exposures, including antibiotic use and dietary patterns during childhood, may alter gut microbiota and increase cancer risk 1
• Increasing rates of inflammatory bowel disease among younger populations may contribute to early onset cases 1

Recommendations for Screening and Management

• Initiating screening colonoscopy at age 45 years instead of 50 years is recommended for individuals at average risk for CRC, with varying strength of evidence 1
• Individuals with a family history of CRC and/or adenomas have an increased risk of CRC and should undergo screening earlier, with the age of initiation depending on the age at diagnosis of affected relatives 1
• Patients with BMMRD are at risk for extremely early onset CRC and should undergo colonoscopy every 1–2 years, beginning between ages 20–25 years or 2–5 years before the youngest age at diagnosis of CRC in the family if diagnosed before age 25 years 1

From the Research

Etiology of Early Onset Colon Cancer

The etiology of early onset colon cancer is complex and involves both genetic and environmental factors.

• Genetic factors:
  • Lynch syndrome and Familial Adenomatous Polyposis are well-known genetic syndromes that increase the risk of colon cancer 2, 3
  • Sporadic early-onset colorectal cancer exhibits a broad spectrum of pathogenic germline mutations, genetic polymorphisms, methylation changes, and chromosomal instability 4
• Environmental factors:
  • Early-life exposures and lifestyle factors, such as diet and physical activity, have been found to be associated with early-onset colorectal cancer risk 4, 5
  • Specific chronic diseases, such as inflammatory bowel disease, diabetes, and metabolic syndrome, have been associated with early-onset colorectal cancer 4, 5

Risk Factors for Early Onset Colon Cancer

Several risk factors have been identified for early-onset colon cancer, including:

• Demographic factors:
  • Male sex (OR=1.20; 95% CI, 1.08-1.33) 5
  • Caucasian ethnicity (OR=1.44; 95% CI, 1.15-1.80) 5
• Chronic conditions:
  • Family history of CRC (OR=5.90; 95% CI, 3.67-9.48) 5
  • Inflammatory bowel disease (OR=4.43; 95% CI, 4.05-4.84) 5
  • Obesity (OR=1.52; 95% CI, 1.20-1.91) 5
  • Overweight (OR=1.18; 95% CI, 1.12-1.25) 5
  • Hypertension (OR=1.16; 95% CI, 1.12-1.21) 5
  • Metabolic syndrome (OR=1.29; 95% CI, 1.15-1.45) 5
• Lifestyle factors:
  • Smoking (OR=1.44; 95% CI, 1.10-1.88) 5
  • Alcohol consumption (OR=1.41; 95% CI, 1.22-1.62) 5
  • Sedentary lifestyle (OR=1.24; 95% CI, 1.05-1.46) 5
  • Western dietary patterns (OR=1.43; 95% CI, 1.18-1.73) 5
  • Red meat (OR=1.10; 95% CI, 1.04-1.16) 5
  • Processed meat (OR=1.53; 95% CI, 1.13-2.06) 5
  • Sugar-sweetened beverages (OR=1.55; 95% CI, 1.23-1.95) 5

Gene-Environment Interactions

Gene-environment interactions have been found to play a role in the development of colorectal cancer, with some studies suggesting that certain genetic variants may increase the risk of colorectal cancer in the presence of specific environmental factors 6