Colorectal cancer causes
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To view the causes of familial adenomatous polyposis (FAP), click here
To view the causes of hereditary nonpolyposis colorectal cancer (HNPCC), click here
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: ; Fahad Hasan, M.D.[2] Roukoz A. Karam, M.D.[3] Saarah T. Alkhairy, M.D.
Overview
Colorectal cancer has no single cause. It develops through a stepwise build-up of genetic and epigenetic changes that turn normal colonic epithelium into adenocarcinoma, usually over 10–15 years.[1] Three overlapping molecular pathways account for nearly all cases:
- the chromosomal instability (CIN) pathway
- the mismatch repair–deficient/microsatellite instability (dMMR/MSI) pathway
- the serrated neoplasia pathway, which is linked to BRAF mutation and the CpG island methylator phenotype (CIMP)[2][3]
Germline defects in these same pathways cause the hereditary colorectal cancer syndromes. The best known are Lynch syndrome (germline mismatch repair genes) and familial adenomatous polyposis (germline APC).[4][5]
The pathway a tumor follows has clinical consequences. It determines:
- tumor location and precursor lesion type
- microsatellite status
- whether an MSI-high tumor is sporadic or Lynch-associated[2][6]
Causes
Molecular Pathways of Colorectal Carcinogenesis
The three pathways differ in the type of genomic instability and the precursor lesion.[2][3][1] The proportions below overlap and add up to more than 100%. This is because serrated-pathway tumors can become either MSI-high (through MLH1 methylation) or microsatellite-stable.[5]
| Feature | Chromosomal instability (CIN) | Mismatch repair deficiency (dMMR/MSI) | Serrated neoplasia (CIMP) |
|---|---|---|---|
| Approximate share of CRC | ~70–85%[3][7] | ~15%[3][6] | ~15–20%[2][8] |
| Precursor lesion | Conventional adenoma (adenoma–carcinoma sequence) | Adenoma; in MLH1 Lynch carriers possibly no visible polyp ("shortcut" route) | Sessile serrated lesion or traditional serrated adenoma |
| Initiating event | Biallelic APC inactivation (less often CTNNB1 activation) | Germline MMR variant plus second hit (Lynch), or somatic MLH1 promoter hypermethylation (sporadic) | BRAF V600E mutation |
| Key later events | KRAS/NRAS, PIK3CA, 18q loss (SMAD4/DCC), TP53 | Frameshift mutations in coding microsatellite genes (TGFBR2, ACVR2A, BAX) | CIMP-driven silencing of tumor suppressor genes, including MLH1 |
| Microsatellite status | Microsatellite-stable (MSS) | MSI-high | MSI-high (when MLH1 is methylated) or MSS |
| Typical location | Left colon and rectum | Variable | Right (proximal) colon |
Chromosomal Instability Pathway
- This is the classic adenoma–carcinoma sequence and the most common route to CRC.[3][7]
- Initiation: biallelic loss of the APC tumor suppressor (or, less often, an activating CTNNB1/β-catenin mutation) switches on WNT/β-catenin signaling without control. The first visible lesion is the aberrant crypt focus.[3][7][2]
- Progression: changes then accumulate in order:
adenoma: KRAS or NRAS and PIK3CA mutations, and loss of heterozygosity at 18q (SMAD4/DCC)
invasive carcinoma: TP53 mutation marks the transition.[3][9][10] - CIN tumors are usually MSS, occur more often in the left colon and rectum, and fall mainly into consensus molecular subtypes CMS2–CMS4.[3]
Mismatch Repair–Deficient (MSI) Pathway
- Cause: loss of DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2). This happens in one of two ways:
germline: a pathogenic variant (Lynch syndrome)
sporadic (more common): somatic MLH1 promoter hypermethylation.[3][7][6] - Consequence: a hypermutated tumor. Frameshift mutations build up in genes that contain coding microsatellites, such as TGFBR2, ACVR2A and BAX, and speed up progression.[4]
- The route differs by gene in Lynch syndrome:[11]
- MSH2-associated tumors usually carry somatic APC mutations (75% vs 11% in MLH1-associated tumors).
- MLH1-associated tumors more often carry somatic CTNNB1 mutations (50% vs 7%).
- "Shortcut" carcinogenesis in MLH1 carriers: some of these cancers may arise directly from MMR-deficient crypts without a visible polyp stage. One proposed model is a "two-in-one hit": a single event (mitotic recombination on chromosome 3p) both inactivates the remaining MLH1 allele and activates CTNNB1.[12][6]
Serrated Neoplasia Pathway
- Precursors: sessile serrated lesions and traditional serrated adenomas, not conventional adenomas.[2][8]
- Initiating event: activating BRAF V600E mutation, which drives constant MAPK signaling. It is present in most sessile serrated lesions.[2][10]
- Progression: the CpG island methylator phenotype (CIMP) silences tumor suppressor genes. Silencing of MLH1 produces sporadic MSI-high CRC.[2][10]
- APC mutations are uncommon in this pathway (~8% in one review), which separates it from the CIN route.[10]
- Serrated-pathway tumors are strongly associated with:
Hereditary Colorectal Cancer Syndromes
A minority of colorectal cancers arise from a monogenic germline predisposition.[5][4]
| Syndrome | Germline gene(s) | Mechanism and colorectal phenotype |
|---|---|---|
| Lynch syndrome | MLH1, MSH2, MSH6, PMS2; EPCAM deletions (silence MSH2) | Most common hereditary CRC syndrome; autosomal dominant constitutional MMR deficiency.[6][4] 10-year CRC risk under surveillance is similar in MLH1 and MSH2 carriers (11.3% vs 11.4%) and lower in MSH6 carriers (4.7%). MSH2 carriers have a higher 10-year risk of advanced adenoma than MLH1 carriers (17.8% vs 7.7%).[11] |
| Familial adenomatous polyposis (FAP) | APC | Constitutive WNT activation; hundreds to thousands of colonic adenomas, with near-universal progression to CRC if untreated.[4][7] |
| Polymerase proofreading–associated polyposis | POLE, POLD1 (monoallelic) | Ultramutated tumor phenotype.[14] |
| Serrated polyposis syndrome | Rare germline RNF43 variants | Serrated-pathway polyposis; a germline cause is found in only a minority of patients.[14] |
Sporadic Versus Hereditary MSI-High Tumors
MSI-high status alone does not establish Lynch syndrome. Most sporadic MSI-high CRCs arise through the serrated pathway, via somatic MLH1 promoter methylation, and carry BRAF V600E.[2][6] MSI-high tumors that are BRAF wild-type and lack MLH1 methylation suggest a germline MMR cause.[2][6]
Inflammation-Associated Carcinogenesis
The inflammatory tumor microenvironment, made up of immune cells, stromal cells and the intestinal microbiome, shapes colorectal tumorigenesis.[9][10] How much the microbiome and inflammation contribute to starting the CIN pathway versus the serrated pathway is not well established.[10]
Areas of Uncertainty
- The exact mechanism of adenoma-skipping ("shortcut") carcinogenesis in MLH1-associated Lynch syndrome is not fully defined. It is relevant to why colonoscopic surveillance may protect MLH1 carriers less well.[12][6]
- No single standardized marker panel defines CIMP across studies, which makes studies hard to compare.[2]
References
- ↑ 1.0 1.1 Dekker E, Tanis PJ, Vleugels JLA, Kasi PM, Wallace MB (2019). "Colorectal cancer". Lancet. 394 (10207): 1467–1480. doi:10.1016/S0140-6736(19)32319-0.
- ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 Nguyen LH, Goel A, Chung DC (2020). "Pathways of colorectal carcinogenesis". Gastroenterology. 158 (2): 291–302. doi:10.1053/j.gastro.2019.08.059. PMID 31622622.
- ↑ 3.0 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 Kennel KB, Greten FR (2025). "The immune microenvironment of colorectal cancer". Nat Rev Cancer. 25 (12): 945–964. doi:10.1038/s41568-025-00872-1.
- ↑ 4.0 4.1 4.2 4.3 4.4 Lynch HT, de la Chapelle A (2003). "Hereditary colorectal cancer". N Engl J Med. 348 (10): 919–932. doi:10.1056/NEJMra012242. PMID 12621137.
- ↑ 5.0 5.1 5.2 Kim JC, Bodmer WF (2022). "Genomic landscape of colorectal carcinogenesis". J Cancer Res Clin Oncol. 148 (3): 533–545. doi:10.1007/s00432-021-03888-w.
- ↑ 6.0 6.1 6.2 6.3 6.4 6.5 6.6 6.7 Curtius K, Gupta S, Boland CR (2022). "Review article: Lynch syndrome—a mechanistic and clinical management update". Aliment Pharmacol Ther. 55 (8): 960–977. doi:10.1111/apt.16826.
- ↑ 7.0 7.1 7.2 7.3 7.4 Lizarbe MA, Calle-Espinosa J, Fernández-Lizarbe E, Fernández-Lizarbe S, Robles MÁ, Olmo N, Turnay J (2017). "Colorectal cancer: from the genetic model to posttranscriptional regulation by noncoding RNAs". Biomed Res Int. 2017: 7354260. doi:10.1155/2017/7354260. PMID 28573140.
- ↑ 8.0 8.1 8.2 8.3 IJspeert JE, Vermeulen L, Meijer GA, Dekker E (2015). "Serrated neoplasia—role in colorectal carcinogenesis and clinical implications". Nat Rev Gastroenterol Hepatol. 12 (7): 401–409. doi:10.1038/nrgastro.2015.73.
- ↑ 9.0 9.1 Schmitt M, Greten FR (2021). "The inflammatory pathogenesis of colorectal cancer". Nat Rev Immunol. 21 (10): 653–667. doi:10.1038/s41577-021-00534-x.
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 Permain J, Hock B, Eglinton T, Purcell R (2024). "Functional links between the microbiome and the molecular pathways of colorectal carcinogenesis". Cancer Metastasis Rev. 43 (4): 1463–1474. doi:10.1007/s10555-024-10215-5.
- ↑ 11.0 11.1 Engel C, Ahadova A, Seppälä TT; et al. (2020). "Associations of pathogenic variants in MLH1, MSH2, and MSH6 with risk of colorectal adenomas and tumors and with somatic mutations in patients with Lynch syndrome". Gastroenterology. 158 (5): 1326–1333. doi:10.1053/j.gastro.2019.12.032. PMID 31926173.
- ↑ 12.0 12.1 Ahadova A, Stenzinger A, Seppälä T, Hüneburg R, Kloor M, Bläker H; Lynpath Investigators (2023). "A "two-in-one hit" model of shortcut carcinogenesis in MLH1 Lynch syndrome carriers". Gastroenterology. 165 (1): 267–270.e4. doi:10.1053/j.gastro.2023.03.007. PMID 36907525 Check
|pmid=value (help). - ↑ He X, Wu K, Ogino S; et al. (2018). "Association between risk factors for colorectal cancer and risk of serrated polyps and conventional adenomas". Gastroenterology. 155 (2): 355–373.e18. doi:10.1053/j.gastro.2018.04.019.
- ↑ 14.0 14.1 Sommer AK, Te Paske IBAW, Jansen EAM; et al. (2026). "Mutational landscape of colorectal tumors from individuals with unexplained adenomatous or serrated colorectal polyposis". Gastroenterology. 170 (3): 557–568. doi:10.1053/j.gastro.2025.10.011.