Novel genetic and epigenetic alterations in ... - Ous-research.no

Introductionexemplified by frequent mutations in specific regions of TP53 * , KRAS, BRAF and PIK3CA † .This can be explained by selection pressure and clonal growth advantage[11]. If a mutationgives the cell a growth advantage it will have higher fitness compared to surrounding cells,leading to selection in accordance with the evolution theory[20]. On the same basis, , a cellwith a “non-important” mutation, often denoted passenger mutation, will not have increasedlikelihood of passing the acquired trait to its daughter cells. In the largest available mutationdatabase, Catalogue Of Somatic Mutations In Cancer (COSMIC), ~4800 of our 20-25000genes are included[21], a number which also includes a large number of genes with noobserved mutations. The number of genes which is essential for tumor formation is muchlower, and it has been estimated that just more than 1% of the human genes can beattributed “cancer critical” genes, as these are known to be involved in carcinogenesis[22].DNA methylationMethylation is one of many possible chemical modifications of the double helix. At a CpGdinucleotide, a cytosine followed by a guanine, a methyl group can covalently bind to the5’position of cytosine, constituting a 5-methylcytosine, first described in 1948[23]. This willserve as a recognition mark for methyl binding proteins. The CpG dinucleotide is greatlyunderrepresented in the human genome due to spontaneous deamination of 5-methylcytosine throughout the evolution, causing a cytosine to thymine change that escapesthe DNA repair systems[24]. Hence, the remaining CpG-sites are mainly located in areaswith a close to theoretically expected amount of CpG, called CpG-islands, but are alsopresent within repetitive sequences. These islands are located in the 5’-ends of about half ofour genes and are under normal circumstances protected against methylation[25].Both establishment and maintenance of methylation marks are governed by DNA methyltransferases (DNMTs). During DNA replication hemi-methylated DNA is recognized byDNMT1, and the methylation marks of the initial strand are copied to the nascent DNAstrand, ensuring a faithful inheritance of DNA methylation patterns in the daughter cells.This process is called maintenance methylation. DNMT3A and DNMT3B handle the de novo* IARC TP53 database – http://www-p53.iarc.fr/† Catalogue of Somatic Mutations in Cancer database – http://www.sanger.ac.uk/genetics/CGP/cosmic/15