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

Introductionthere seems to be a fidelity threshold for homopolymer tracts, where those longer than 7base pairs are considered much less stable than those of seven or fewer units[80].With well over a thousand genes containing eight or more mononucleotide repeats in thegenome[90] it is obvious that mutations in these genes will accumulate at a much higher rateamong MSI tumors compared to tumors with a functional MMR-system. MSI is thereforeoften referred to as the mutator phenotype[91].CpG island methylator phenotype – CIMPWhile CIN tumors have a defect in the chromosomal segregation and MSI tumors have adefective MMR-system, the CIMP-tumors have a methylation machinery that has gone awry,causing epigenetic instability[92]. Tumors with CIMP are therefore associated with promoterhypermethylation of a large number of genes. It has previously been shown that 38% ofCRC display neither CIN nor MSI, and it has been speculated whether this group hasepigenetic events as the malignant driving force[93]. The CIMP phenotype overlaps in alarge degree with MSI, resulting in many of the same clinical associations, such as proximallocation and female gender of old age[92]. Overall, CIMP is associated with a poor prognosiscompared to CIMP-negative tumors[94;95]. In addition, it has been shown to be anindependent (from MSI and TP53 mut ) positive predictor of survival benefit from 5-FUtreatment[96]. On the genetic level, CIMP is strongly associated with the V600E mutation inBRAF, KRAS mut , and TP53 wt [97;98], which has led to the suggestion of two CIMP-groups;CIMP1 which is associated with extensive hypermethylation, V600E mutation in BRAF andMSI; CIMP2, an intermediate group with less frequent hypermethylation than CIMP1 as wellas KRAS mutation; and the CIMP negative group which contains very scarce methylation,microsatellite stable and wild-type TP53 tumors[98](Figure 11). CIMP is inversely associatedwith mutations in APC, the hallmark of early events in adenomas[99], thus supporting thehypothesis that CIMP and MSI tumors originate from the sessile serrated polyps and notadenomas[100]. CIMP is not exclusive for CRC. It has also been shown in gastric-, lung-,liver- and ovarian cancer as well as leukemia[95].30