Somatic genomic imbalances, LOH and methylation

Coordinator:		Prof. Dr. Reiner Siebert
Institution:		Institut für Humangenetik, UK-SH
Homepage:		www.uni-kiel.de

Applying up to date microarray technologies, we will identify both genomic alterations and aberrations in the DNA-methylation pattern of colorectal carcinoma cells and determine their impact on tumor initiation and progression.
Each single cell of the body contains two copies of the complete genetic code. However, only a selection of genes will be activated in a tissue specific manner in each cell, allowing the differentiation into the different cell types of our body. One mechanism regulating gene expression is the enzymatic methylation of cytosine residues in the DNA. Based on the defined copy number of each gene these molecular regulation processes control gene activity and as a consequence the interplay of genes either inducing cell division or differentiation. Dysfunction of this interplay or failure of gene regulation can result in enhanced and unregulated cell division. As a consequence, normal tissue will be displaced, and the growing tumor starts interfering with the normal function of the organ.
Numerous mechanisms interfere with normal gene expression in tumor cells. One option is the aberrant methylation of the DNA. Hypomethylation can lead to activation of oncogenes and hypermethylation of the DNA can result in the repression of genes usually preventing cell division. Another mechanism interfering with gene expression in tumor cells is the change of the copy number of genes. Single DNA sequences or even whole chromosomes containing essential genes for controlling cell division and growth can either be amplified or lost during tumorigenesis.
Both mechanisms contribute significantly to the development of colorectal cancer. Initial aberrations are mostly already detectable in tumor progenitor cells before the cell degenerates into a malignant tumor cell. By investigating both, genomic imbalances and aberrations in the DNA methylation pattern in colorectal cancer it is the aim of this project determining the impact of these alterations for tumor progression and to make use of the results to develop new tests for the early detection of this devastating disease. An early detection at an early state of tumorigenesis is of special interest since tumor state at diagnosis correlates significantly with the prognosis and the success of therapy.