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Genesis and Progression of GI Cancer – a Genetic Disease

Chapter 1 - Biology of Cancer Development in the GI Tract

Colorectal Cancer

Fearon and Vogelstein proposed a genetic model to explain the stepwise formation of colorectal cancer (CRC) from normal colonic tissues.

The model states: (1) CRC results from mutations in genes with important functions in regulating cell proliferation or DNA repair, (2) mutations in >1 gene are required, and (3) the sequence of mutations is important in determining the formation of CRC.

These altered genes can be divided into two classes: tumour suppressors that either inhibit cell proliferation or promote apoptosis, and oncogenes that promote cell proliferation and tumour progression.

Phylogenetically, CRCs can be divided into two molecular subtypes: those with chromosomal instability (CIN) and those with microsatellite instability (MSI).

Carcinomas with MSI present cancer-initiating mutations that inactivate the function of mismatch repair (MMR) genes (e.g. MSH2, MSH6, MLH1 and PMS2) leading to hypermutated genomes. This is known as the “mutator phenotype”. MSI tumours frequently present a CpG island methylator phenotype (CIMP) leading to the repression of tumour suppressor genes including MLH1.

Revision Questions

  1. Is MSI always related to hereditary colon cancer?
  2. Can you comment on potential therapies for hypermutated colon cancer?
  3. Can you mention three genes involved in the chromosomal instability pathway?
Editors and Contributors Genesis and Progression of GI Cancer – a Genetic Disease - Gastric, Pancreatic Cancer

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