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

DiscussionDifferent origins of colorectal cancer contribute to a non-uniform diseaseAs mentioned earlier there is increasing evidence that CRC is not a uniform disease, and thatthere are at least two distinct routes causing it, the traditional adenoma-carcinoma pathwayand the newer pathway through HPs and sessile serrated adenomas (page 25-26). There areseveral indications also in the present studies supporting the theory that MSI tumorsoriginate from sessile serrated adenomas and not traditional adenomas. If adenomas gaverise to both MSS and MSI tumors one would expect close to a similar frequency of MSIadenomasas MSI-carcinomas (~12-15%). In paper II, 63 adenomas were included in whichonly 2 were MSI (3%). In addition, the majority of sporadic MSI tumors are caused byMLH1 hypermethylation. None of the adenomas in our study, not even the two with MSIcontained hypermethylation of this gene. Also, the 5 genes almost exclusively methylated inMSI-tumors (CRABP1, MLH1, NR3C1, RUNX3 and SCGB3A1) displayed very low, orabsent, methylation frequencies in adenomas, supporting the fact that MSI tumors areunlikely to originate from adenomas. In parallel, we have analyzed the same genes as in paperII for promoter hypermethylation in 12 hyperplastic polyps (HPs) as well as determinedmutation status of BRAF (data not included). The HPs were significantly more frequentlymethylated than the adenomas, and when comparing HPs and MSI tumors, similarmethylation frequencies were observed across all genes. Also, 50% of the HPs carried aV600E mutation in BRAF. Only one of the HPs displayed MSI, consistent with the sessileserrated pathway theory in which mutation in BRAF is the initiating event while MSI is a lateevent[71]. Together these data show that the HPs already carry alterations typical for MSItumors,while the adenomas do not, hence supporting the aforementioned theory.63