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

Introductioninasmuch as 80% of colorectal tumors [64]. Activation of the proto-oncogene KRAS is alsoconsidered an early event, and is present in 35% of colorectal carcinomas ** . TP53, called “theguardian of the genome”[66] is a critical component in sensing DNA damage and stresssignals, and is the most frequently altered tumor suppressor gene in human cancer in general.In colorectal cancer it is not altered until late in the development, in advanced carcinomas,and close to 50% of all CRC have mutations in TP53 at this stage †† . According to this model,microsatellite instability is a late event as it is only seen in advanced adenomas andsubsequent stages[64].Compelling evidence in recent years have questioned this paradigm and turned the scaletowards adenomas giving rise only to chromosome instable and CIMP-negative tumors,while the previously “ignored” hyperplastic polyps (HPs) have re-established their malignantpotential, as a subgroup of these, the sessile serrated polyps, are likely to give rise to MSI andCIMP tumors[67-70]. An equivalent to the adenoma-carcinoma sequence has now beensuggested and includes the development from normal mucosa via HPs and serrated lesionsto MSI-carcinomas. Typical for these cancers is that mutation in the proto-oncogene BRAFis considered the “gatekeeper”, and that the dysregulation of the methylation machineryoccurs before microsatellite instability (Figure 10)[71].Hypermethylation in normal-appearing colorectal mucosa adjacent to the primary tumorshas gained interest lately. This abnormality is thought to be the initiating event intumorigenesis, as it presents a field in which the cells are especially susceptible for additionalalterations. With a sufficing amount of alterations, the tumorigenesis is initiated. Thisphenomenon is called “field effect” or “field cancerization”, and several genes have beensuggested to generate such[72-75].** Catalogue of Somatic Mutations in Cancer database – http://www.sanger.ac.uk/genetics/CGP/cosmic/†† IARC TP53 Mutation Database (Release 12) - http://www-p53.iarc.fr/26