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

DiscussionIn paper IV, our aim was to identify markers in MSI-carcinomas that carry prognosticinformation. This patient group accounts for about 15% of all CRC patients and areassociated with an improved disease outcome compared to that of CRC as a whole. Deathfrom cancer can be a crude measurement as risk of relapse from disease is an importantfactor when evaluating who would benefit from adjuvant chemotherapy. Hence, disease-freesurvival was chosen as clinical end-point in order to include both death from cancer andrelapse.Driver and passenger (epi)mutationsMutations and epigenetic alterations are frequent in human tumors, but most likely not allalterations are important for tumor development. The discrimination between driver andpassenger, or bystander, mutations has gained increased interest the last decade. Thealterations which give the cell a growth advantage will be selected, denoted driver mutations,while the background noise of mutations that confer no clonal growth advantage are termedpassenger mutations[201]. When screening large numbers of genes, and especially with themodern ultra high throughput systems, this discrimination is important.Several methods are applied in order to separate the passengers from the drivers, most oftenby use of statistical and probability calculations. Simplified one can say that if a mutationoccurs more often than what would be expected by chance, it indicates a positive selectionwhile a more seldom occurrence indicates a negative selection pressure[201-203]. A study bySjöblom and co-workers included 13023 genes, among which they found over a thousand tobe mutated in colorectal and breast cancer. Among those, only 189 were considered to begenes with impact on tumorigenesis, with an average of 9 mutated genes per colorectalcarcinoma[202].The concept of driver and passenger mutations is especially important in tumors with MSI,or the mutator phenotype. The mutability of mononucleotide repetitions within MSI-tumorsdepends primarily on structural factors. Because of the high background of genetic instabilityit is challenging to establish which of these alterations plays a role in tumorigenesis. Duvaland co-workers has suggested two schemes to divide the genes into driver and by-stander61