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Genetics of colorectal cancer

I. Kotzev, M. Mirchev


Colorectal cancer is one of the commonest neoplastic disorders in humans, and a major cause of cancer related deaths. It is divided into sporadic, familial, and hereditary. Three major groups of genes participate in its pathogenesis: tumor suppressor genes, oncogenes, and mismatch repair genes. The function of tumor suppressor genes was discovered by Knudson in his ‘two hit` hypothesis, and Fearon and Vogelstein proposed their model for ‘multistep carcinogenesis`, responsible for the widely known adenoma-carcinoma sequence. From the inherited syndromes Familial Adenomatous Polyposis (to inborn mutation in the APC gene) and Herediraty Nonpolyposis Colorectal Cancer (is caused by inherited mutations in the mismatch repair genes, leading to microsatellite instability) lead to early onset of colorectal cancer. Recent studies revealed that sporadic colorectal cancer occurs in two distinct pathways, the first one being chromosomal instability, corresponding to FAP, and the second one named microsatellite instability, which corresponds to HNPCC. Today it is known that most of the sporadic cases, exhibiting microsatellite instability, are caused by promoter hypermethylation of MLH1 gene, leading to its inactivation. DNA methylation is an epigenetic phenomenon occurring normally in the cell and in large number of processes. It is not well studied, and could discover participation of other genes in colorectal tumorigenesis. RUNX3 gene, whose promoter hypermethylation is responsible for gastric cancer, is a member of RUNT family of transcription factors, taking part in TGFb mediated signal transduction, whichis of ten deregulated in tumors exhibiting microsatellitein stability. It would be interesting to find out whether certain clinicopathological features, such as proximal tumor location, low grade of differentiation, mucinous histology, and intratumoral lymphocyte infiltration could differentiate tumors showing promoter hypermethylation from those lacking these features.

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About The Authors

I. Kotzev
Medical University of Varna

Clinic of Gastroenterology

M. Mirchev
Medical University of Varna

Clinic of Gastroenterology

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