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Reliable, easy-to-read patient information on common medical conditions — written in plain language, free of jargon, and grounded in current evidence. Browse the most frequent diagnoses, understand what they mean for everyday life, and learn which steps and questions help you have a focused conversation with your doctor.

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Colorectal cancer causes

Introduction

Overview

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

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]

Principal molecular pathways of colorectal carcinogenesis
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:
    • right-sided location[8]
    • smoking, which is more strongly linked to serrated lesions than to conventional adenomas[13]
    • a disproportionate share of post-colonoscopy (interval) cancers[8]

Hereditary Colorectal Cancer Syndromes

A minority of colorectal cancers arise from a monogenic germline predisposition.[5][4]

Hereditary syndromes covered in the source material
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

References

  1. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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. ↑ 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).
  13. ↑ 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. ↑ 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.

Editor-In-Chief: To view the causes of familial adenomatous polyposis (FAP), click here
To view the causes of hereditary nonpolyposis colorectal cancer (HNPCC), click here

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.