What Causes Rectal Cancer?
Rectal cancer develops through a complex interplay of genetic mutations (primarily via the chromosomal instability pathway), hereditary factors, and modifiable lifestyle/environmental exposures, with the majority of cases arising from accumulated DNA damage in colonic epithelial cells over time. 1
Molecular and Genetic Mechanisms
Primary Pathways of Development
- The majority of rectal cancers develop via the chromosomal instability (CIN) pathway, involving sequential accumulation of genetic mutations in tumor suppressor genes and oncogenes 1
- The WNT signaling pathway is the most important molecular pathway in rectal cancer carcinogenesis, with frequent mutations in the APC tumor suppressor gene 1
- Inactivation of tumor suppressor genes in the P53 and TGFβ pathways occurs, along with activation of oncogenes such as KRAS and PI3CKA 1
- About 13% of rectal cancers are caused by deficient mismatch repair (dMMR), though microsatellite instability is very rare in rectal cancer specifically (only a few percent) 1, 2
- Approximately one-third of rectal cancers are associated with aberrant DNA methylation 1
- BRAF mutations are rare in rectal cancer, distinguishing it from colon cancer 1
Hereditary Component
- Up to 15% of rectal cancer cases have a hereditary component, though this is more pronounced for colon cancer than rectal cancer 1, 2
- The most common hereditary disorders are Lynch syndrome and familial adenomatous polyposis, warranting genetic counseling for affected families 1
- Approximately 40 common, low penetrance CRC risk alleles have been identified, with higher penetrance rare variants accounting for an additional 16% of hereditary risk 1
Modifiable Risk Factors
Dietary Factors
- Excessive consumption of red or processed meat increases rectal cancer risk 1
- Dietary fiber most likely decreases the risk of rectal cancer 1
- Consumption of garlic, milk, calcium, and high dietary fiber are regarded as protective 1
- High-quality diets assessed by diet quality indices are associated with lower CRC risk 1
Lifestyle Factors
- Tobacco smoking increases the risk of rectal cancer 1
- Moderate to heavy alcohol use increases rectal cancer risk 1
- Physical inactivity is a significant risk factor, while a healthy lifestyle and regular exercise can substantially reduce risk 1
- High body mass index, body or abdominal fatness increase the risk 1
Metabolic Factors
- Diabetes type II increases rectal cancer risk, with a probable causal role of hyperinsulinemia and insulin-like growth factors 1
Medical Conditions That Increase Risk
- Longstanding ulcerative colitis and Crohn's disease affecting the rectum increase the risk of rectal cancer 1
- The inflammatory bowel disease-cancer association is well-established and forms the basis for colonoscopic surveillance recommendations 3
Age and Demographics
- Risk increases with age, with median age at diagnosis being approximately 70 years 1
- The incidence is predicted to increase further in both genders, with median age at diagnosis expected to rise 1
Protective Factors
- Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced incidence, though no formal guidelines for pharmacological primary prevention exist 1
- There may be a protective effect of vitamin D via antitumor immunity, though evidence remains mixed regarding supplementation 1
Important Distinctions from Colon Cancer
- Evidence is accumulating that rectal cancer is distinct from colon cancer with different etiologies and risk factors, possibly reflecting different environmental exposures 1, 2
- Unique transcriptional subtypes with high Wnt signaling, stem cell and mesenchymal signatures occur specifically in rectal cancer and carry a poor prognosis 2
Clinical Pitfalls
The interaction between genetic susceptibility, gut microbiome, epigenetics, and environmental factors remains poorly characterized 1. Much of the "missing heritability" remains unidentified, emphasizing that our understanding of rectal cancer causation is incomplete and continues to evolve.