Colon Carcinoma

 1. Colon Carcinoma The model of stepwise genetic alterations in cancer is best illustrated by observation of colonic lesions at different stages of progression to malignancy. Certain genetic alterations are found commonly in early-stage adenomas, whereas others tend to occur more frequently at later stages of tumorigenesis or after the development of invasive carcinoma. The timeline of genotypic and phenotypic changes during the development of colon cancer .These changes are in keeping with the concept that serial phenotypic changes, driven by serial genetic alterations, must occur in a cell for it to exhibit full malignant (invasive and metastatic) properties.

The earliest molecular defect in the pathogenesis of colon cancer is activation of the Wnt signaling pathway, which occurs through the development of somatic mutations in the APC tumor suppressor gene in the normal colonic mucosa. This leads to abnormal cell proliferation and the initial steps in neoplasia that lead to formation of polyps in the colon. 

At an early point in polyp formation, growth factor receptor signaling pathways are activated. This occurs through mutational activation of the KRAS, NRAS, or BRAF signal transduction oncogenes, which further remove restraints on cell proliferation and enable polyps to grow bigger. 

The next step in tumorigenesis are mutations in genes involved in the TGF-β signaling pathway. This further deregulates growth patterns and properties of enlarging polyps.

 Deletion or loss of expression of the DCC gene is common in the progression to invasive colon cancers. The DCC protein is a transmembrane protein of the immunoglobulin superfamily and may be a receptor for certain extracellular molecules that guide cell growth and/or apoptosis.  

Mutational inactivation of TP53 disrupts cell cycle checkpoints, staves off apoptosis, and occurs at a late stage in the progression to an invasive cancer phenotype. The genes specifically responsible for subsequent progression to a metastatic phenotype are not yet well understood. In parallel to these sequential abnormalities in the regulation of cell proliferation, colon cancers also acquire defects in mechanisms that protect genomic stability. These generally occur along one of two mechanisms. 

In some colon cancers, the abnormalities are a result of mutations in mismatch repair genes. Mismatch repair genes are a family of genes involved in “proofreading” DNA and correcting incorporation errors during replication; they include MSH2, MLH1, PMS1, and PMS2. 

Tumors with mutations in mismatch repair genes perform DNA replication with many errors, and thus these tumors develop thousands of mutations, resulting in what is referred to as a hypermutator phenotype. This phenotype can be detected by a PCR-based microsatellite instability (MSI) assay in which the hypermutator tumor phenotype will test MSI high. 

In colon cancers that are not MSI high, genomic instability occurs as a result of mutations in chromosomal instability (CIN) genes. Because of their impaired ability to preserve chromosome structure and content, these tumors have losses or gains of large segments of chromosomes or entire chromosomes and are highly aneuploid. 

The stepwise acquisition of genetic abnormalities described above is associated with alterations in the phenotypic behavior of the colonic mucosa. The earliest change in the progression to colon cancer is an increase in cell number (hyperplasia) on the epithelial (luminal) surface. This produces an adenoma, which is characterized by gland-forming cells exhibiting increases in size and cell number but no invasion of surrounding structures . Presumably, these changes are a result of enhanced proliferation and loss of cell cycle control but occur before acquisition of the capacity to invade the ECM. 

Additional dysplastic changes, such as loss of mucin production and altered cell polarity, may be present to a variable degree. Some adenomas may continue to enlarge and ultimately progress to invasive carcinoma. 

An early feature associated with disrupted architecture even before invasion occurs is the development of fragile new vessels or the destruction of existing vessels, which can cause microscopic bleeding. This can be screened for clinically with the fecal occult blood tests used for early diagnosis of pre-invasive and invasive colon cancer. 

All phenotypic changes cannot be explained by a known genetic abnormality, nor do all identified genetic alterations have a known phenotypic result. 

However, the stepwise nature of genotypic and phenotypic abnormalities is well established and strongly supports the mechanistic link between these parallel processes.