Pathogenesis of carcinoma colon

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colorectal cancer AND carcinogenesis

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NCI colorectal cancer genetics APC KRAS TP53 mismatch repair pathogenesis

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https://www.cancer.gov/types/colorectal/hp/colorectal-geneti…

Pathogenesis of carcinoma colon

Most colorectal carcinomas are adenocarcinomas. They arise through progressive accumulation of genetic and epigenetic alterations, transforming normal colonic mucosa into a precursor lesion, then invasive carcinoma.

1. Conventional adenoma-carcinoma sequence: chromosomal instability pathway

This is the commonest pathway, responsible for about 65-70% of sporadic colorectal cancers.

Sequence:

Normal mucosa → early adenoma → enlarging adenoma with dysplasia → carcinoma

Molecular event	Main effect
APC loss on chromosome 5q, an early event	Failure to degrade β-catenin → activation of WNT signaling → increased crypt-cell proliferation and adenoma formation
KRAS activation	Persistent RAS-MAPK signaling → increased growth, survival and progression to larger adenoma
Loss of SMAD2/SMAD4 or other 18q changes	Loss of TGF-β mediated growth inhibition
TP53 loss on chromosome 17p, usually late	Loss of DNA-damage checkpoint and apoptosis → invasion and carcinoma

APC is a tumor-suppressor gene, so both alleles generally must be inactivated. In familial adenomatous polyposis (FAP), one mutated APC allele is inherited and the second hit occurs in colonic epithelial cells, causing hundreds to thousands of adenomas and a very high cancer risk if untreated.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 758.

2. Microsatellite instability pathway: defective DNA mismatch repair

This pathway results from inactivation of DNA mismatch-repair genes:

MLH1
MSH2
MSH6
PMS2

Failure of repair causes accumulation of mutations in short repetitive DNA sequences called microsatellites, producing a high mutational burden.

Lynch syndrome: inherited pathogenic variant in an MMR gene, followed by somatic loss of the remaining normal allele.
Sporadic MSI cancers commonly result from hypermethylation of the MLH1 promoter.

Mutations develop in genes containing microsatellite repeats, including genes involved in growth control and apoptosis, such as TGFBR2 and BAX. These cancers often arise in the proximal colon and may progress from adenomas more rapidly than typical CIN-pathway lesions.

3. Serrated pathway: CpG-island methylator phenotype

Some cancers develop from serrated precursor lesions, especially sessile serrated lesions/adenomas.

Key events are:

Activating BRAF mutation
Widespread promoter CpG-island hypermethylation, called CIMP
Silencing of tumor-suppressor genes, often including MLH1
If MLH1 is silenced, the tumor becomes MSI-high

Thus, the typical serrated pathway is:

Sessile serrated lesion → BRAF mutation + CIMP → MLH1 methylation → MSI-high carcinoma.

The three principal CRC pathways, CIN, MSI, and CIMP/serrated, are also summarized by the NCI genetics review.

4. Role of chronic inflammation

Long-standing inflammatory bowel disease, especially extensive ulcerative colitis and Crohn colitis, can cause chronic cycles of epithelial injury, regeneration, oxidative DNA damage, and cytokine-driven proliferation.

The sequence is usually:

Chronic colitis → flat dysplasia → high-grade dysplasia → carcinoma

Unlike sporadic colorectal cancer, TP53 mutation may occur early in colitis-associated carcinogenesis, while APC mutations are relatively later and less consistent.

5. Environmental and host factors promoting carcinogenesis

These factors do not independently cause cancer but increase the likelihood of mutational accumulation:

Diet high in processed/red meat and fat, low fibre intake
Obesity, insulin resistance and type 2 diabetes
Smoking and alcohol
Increasing age
Family history and inherited syndromes
Chronic inflammatory bowel disease

Low stool bulk and altered microbiota may prolong mucosal exposure to bacterial metabolites and carcinogens. COX-2 is frequently overexpressed in adenomas and carcinomas, promoting prostaglandin-mediated epithelial proliferation.
Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 758.

Exam summary

Colon carcinoma develops mainly through three molecular routes:

CIN / adenoma-carcinoma pathway:
APC → KRAS → SMAD/DCC loss → TP53 loss
MSI pathway:
Defective MLH1, MSH2, MSH6, PMS2 mismatch repair, classically in Lynch syndrome.
Serrated/CIMP pathway:
BRAF mutation + CpG methylation, often causing MLH1 silencing and MSI.

Yamada’s Textbook of Gastroenterology, 7th ed., p. 1579.

Make a flowchart of the pathogensis

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Educational medical flowchart showing the pathogenesis of colorectal carcinoma. Start with normal colonic mucosa, then split into three clear pathways: (1) conventional chromosomal instability adenoma-carcinoma sequence: APC loss/WNT beta-catenin activation to early adenoma, KRAS activation to enlarging adenoma, SMAD2/SMAD4 loss to high-grade dysplasia, TP53 loss to invasive colorectal adenocarcinoma; (2) mismatch repair deficiency pathway: MLH1/MSH2/MSH6/PMS2 defect to microsatellite instability to mutations in TGFBR2 and BAX to carcinoma, labeled Lynch syndrome or sporadic MLH1 promoter methylation; (3) serrated pathway: BRAF activation plus CpG island methylator phenotype to sessile serrated lesion, MLH1 methylation and microsatellite instability to carcinoma. Add a side branch chronic inflammatory bowel disease to chronic inflammation, dysplasia, carcinoma. Use accurate spelling, concise labels, arrows, and a clean white-background exam revision diagram.

Flowchart: Pathogenesis of carcinoma colon

Flowchart of colorectal carcinoma pathogenesis

Exam sequence for the conventional pathway:

Normal colonic mucosa
↓
APC mutation / WNT-β-catenin activation
↓
Early adenoma
↓
KRAS activation
↓
Large adenoma
↓
SMAD2/SMAD4 loss, 18q deletion
↓
High-grade dysplasia
↓
TP53 loss
↓
Invasive colorectal adenocarcinoma

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