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

Discussiongenes. One is based on mutation frequency and suggests that genes with mutationfrequencies below 12% are considered likely to have no functional consequence on tumordevelopment, and therefore entitled by-stander genes[204]. The second scheme is to dividegenes into four categories: survivor genes, hibernator genes, cooperator genes andtransformator genes[205]. Transformator genes confer a positive selection to the cells, havethe highest mutation frequencies, and are most likely to be genes driving tumorigenesis[205].Prior to Paper IV a literature survey was performed[90] and only genes passing certaincriteria, amongst others a mutation frequency exceeding the aforementioned 12% wereincluded. As we aimed to identify prognostic markers we wanted ensure that we did notanalyze mere background artifacts.In the field of epigenetics, genome-wide studies have been performed suggesting that 100-600 genes are subject to promoter hypermethylation in a random tumor[206-208]. Mostlikely, methylation instability, such as CIMP, causes a large number of genes to behypermethylated, and similar to the MSI-tumors, only some of the affected genes exerttumorigenic effects.Whether passenger mutations are just relics of some sort of genome instability andcompletely irrelevant for tumorigenesis or if they apply some minor effect on tumor growthis still questioned. A recent paper argues that for any trait, there will be only a few genes withlarge phenotypic effects, but many associated genes having small effects, although theircombined effect may be substantial[209]. This may be important to keep in mind whendescribing a phenotype, but whether or not the passenger mutations have phenotypic effectsis irrelevant in the case of identifying diagnostic and maybe also prognostic markers, asillustrated by VIM and MAL. Indeed, subsequent to our identification of MAL as apotential biomarker, it has been shown that hypermethylation of MAL is significantlyassociated with improved disease-free survival in gastric cancer[210]. Hence, MAL can berelevant both for diagnosing colorectal cancer and determining prognosis in gastric cancereven though its impact on tumorigenesis is unresolved.62