Colorectal Cancer
ICD-11: 2B90
Disease Overview
Colorectal cancer (CRC) encompasses malignancies arising from the colon or rectum, with adenocarcinoma comprising the majority of cases. Pathogenesis involves the adenoma-carcinoma sequence: accumulated genetic and epigenetic alterations drive progression from normal epithelium through adenomatous polyps to invasive carcinoma. Inherited susceptibility contributes ~35% of CRC risk; major genes include APC (familial adenomatous polyposis), MLH1/MSH2 (Lynch syndrome), and numerous GWAS-identified loci affecting cell-cycle, Wnt signaling, and inflammatory pathways. Diet and the gut microbiome are major environmental modifiers—red meat, processed foods, and low fiber intake increase risk, while the gut microbiota influences inflammation, metabolite production, and DNA damage. Adolescent relevance is emerging: diet quality and obesity established during 10–24 years may shape microbiome composition and epigenetic programming that influences later CRC susceptibility. Early-onset CRC is increasing, highlighting the importance of understanding G×E interactions in younger populations.
Diet and lifestyle patterns established in adolescence influence gut microbiome and metabolic programming; obesity in youth increases later CRC risk. Early-onset CRC is rising; genetic screening for Lynch syndrome may identify at-risk adolescents. Microbiome-establishing exposures during this window may have lasting effects.
Genetic Architecture Summary
| Gene | Variant | GWAS p | Evidence | Strength |
|---|---|---|---|---|
| APC | rs6983267 | 1.5e-11 | Wnt signaling regulator; germline mutations cause FAP; common variants at 8q24 modify CRC risk via enhancer effects on MYC | 0.92 |
| MLH1 | — | — | DNA mismatch repair; germline mutations cause Lynch syndrome; somatic MLH1 silencing in sporadic CRC | 0.9 |
| SMAD7 | rs4939827 | 3.2e-12 | TGF-β signaling inhibitor; variants alter TGF-β pathway and colorectal epithelial homeostasis | 0.82 |
PRS notes: PRS for CRC show moderate discrimination; Lynch syndrome genes excluded from common-variant PRS. Diet-microbiome interactions not incorporated. Transferability to non-European ancestry limited.
Exposure Modifier Panel
| Exposure | Direction | Strength | Confidence | Mechanism hypothesis |
|---|---|---|---|---|
| diet-quality | amplify | 0.85 | HIGH | Low fiber, high red/processed meat amplifies risk; diet shapes gut microbiome and metabolite profile (e.g., secondary bile acids, TMAO); fiber supports butyrate production |
| obesity-exposure | amplify | 0.78 | HIGH | Obesity-driven insulin resistance, adipokines, and chronic low-grade inflammation promote colorectal carcinogenesis; obesity-microbiome interactions |
| tobacco | amplify | 0.65 | MEDIUM | Smoking increases CRC risk; carcinogens reach colonic mucosa; inflammatory and metabolic pathways |
Population Equity Notes
GWAS ancestry breakdown: CRC GWAS heavily European-ancestry; Asian and African ancestry cohorts underrepresented
Transferability notes: APC region associations replicate broadly; Lynch syndrome prevalence varies by ancestry; PRS performance in non-European populations reduced
Data gaps: Multi-ancestry CRC GWAS; microbiome-diet-G×E studies; early-onset CRC genetic architecture
Tissue Context
Mechanism Brief Links
Visualizations
Risk Shift by Exposure Stratum
Population-level data only — does not predict individual risk
Tissue Relevance
References
- 1.Houlston RS, et al. (2008). Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23. Nature Genetics. doi:10.1038/ng.221
- 2.Houlston RS, et al. (2010). Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nature Genetics. doi:10.1038/ng.533
- 3.Gagnière J, et al. (2016). The gut microbiome and colorectal cancer. Gut. doi:10.1136/gutjnl-2015-309897
- 4.O’Keefe SJ. (2016). Diet, gut microbiota, and colorectal cancer. Gastroenterology. doi:10.1053/j.gastro.2016.02.068
- 5.Chan AT, Giovannucci EL. (2010). Gene-environment interactions in colorectal cancer. Gastroenterology. doi:10.1053/j.gastro.2010.04.012