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

Introductionsevere alterations are described in human cancer that can confirm this. On the contrary,germ line mutation in DNMT3B are known to cause ICF syndrome (Immunodeficiencycentromericinstability- facial anomalies syndrome, OMIM #242860), a disease associatedwith hypomethylation of small percentage of the genome[111], but without elevated cancerrisk. Overexpression of DNMT1 has been another suggestion for CIMP development, butdifferent technologies give inconsistent results[95]. Also it has also been speculated whetherloss of methylation boundaries may cause CIMP as methylation naturally increases with age.This age-specific methylation is under normal circumstances kept within its boundaries. Incancer, these boundaries can be lost, leading to spreading of methylation and so-calledcancer-specific methylation[92] ‡‡ .In summary, MSI is the only of the three different instabilities in CRC of which we know thecause, although it seems that the real cause of sporadic MSI is CIMP and that MSI is a mereconsequence of CIMP. (refer Figure 10).Signaling pathwaysThe critical feature in tumorigenesis is often not the altered gene per se, but rather itsinvolvement in a complex signaling network. Alteration in one gene may therefore trigger acascade of signaling factors, such as when KRAS activate the mitogen activated protein(MAP) kinase pathway[112]. Hence, from a cancer cell perspective, it is more beneficial toalter a gene involved in signaling networks instead of a “lonesome wolf”.Some pathways play a more prominent role in tumorigenesis than others, possibly because itis easier for the cell to “highjack” them. The WNT pathway is an example of this. It controlsmany events during embryogenesis, including regulation of proliferation, morphology,motility and cell fate[113]. It is believed to be dysregulated inasmuch as 90% of colorectalcancers and APC, AXIN2, CTNNB1 and TCF7L2 are the most frequently alteredcomponents[114;115]. The MAP kinase pathway, involving KRAS, BRAF, RASSF1A andEGFR as common targets in cancer is another example and is deregulated in at least one‡‡ Jingmin Shu – unpublished – presented on Cancer Epigenetics, AACR Special Conference, Boston, USA,May 200832