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

INTRODUCTIONMicrosatellite instability (MSI) is a phenotype seen in approximately 15% of all colorectalcancers (CRC).[1] It is one of three commonly described phenotypes in CRC alongsidechromosomal instability (CIN), defined by large chromosomal rearrangements andaneuploidy, and CpG Island Methylator Phenotype (CIMP), which denotes tumors withpromoter hypermethylation of a large number of genes.[1] The CIMP tumors show a largedegree of overlap with the MSI tumors.[2] Under normal conditions the DNA mismatchrepair system (MMR) ensures high fidelity DNA replication by preventing insertions anddeletions (indels) of bases caused by replication slippages.[3] Replication slippage commonlyoccurs within microsatellites, which are small stretches of repetitive units varying from 1-6nucleotides scattered throughout the genome.[4] A defective MMR-system, which is theunderlying cause of MSI, will increase the possibility of indels in microsatellites as these arenot repaired successfully. If these microsatellites are located within the coding region of agene this will lead to frameshift mutations,[5] and since many genes have microsatelliteswithin the coding region, MSI is often referred to as the mutator phenotype.[4] There aretwo subgroups within MSI-tumors, those with a low and those with a high degree ofinstability. MSI-L tumors are usually acknowledged to have a phenotype analogous tomicrosatellite stable tumors (MSS).[6]The initial cause of MSI in CRC is most often promoter hypermethylation of the DNAmismatch repair gene MLH1.[7] It is not MSI per se which is the crucial aspect intumorigenesis, but the mutations it generates in genes that may be involved in importantregulatory signaling pathways. Because of the high background of genetic instability in MSI-3