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

DiscussionEven though the subgroup of MSI-tumors as a whole is associated with a relatively goodprognosis, there is still a subgroup within the subgroup with a worse survival. As illustratedin Figure 12, one of our aims is to be able to identify the patients within the MSI-group whoare likely to benefit from a more radical form of treatment, possibly by receiving adjuvantchemotherapy. Some studies have analyzed genes prone to indels of the mononucleotiderepeats in their coding region in association to patient survival. ATR has in a small studybeen associated with improved survival, although not significant[184]. TGFBR2 and BAXare found to be associated with both poor [185] and good prognosis[186]. The reason forthis discrepancy is likely to be caused by small sample sizes (16 and 44 MSI tumors,respectively). Also, the clinical endpoint may affect the results. In the study showingassociation to poor survival, overall survival was used, while the other study failed to definewhat kind of survival endpoint they used. Some studies have analyzed protein expression ofgenes carrying coding mononucleotide repeats and found that low BAX expression isassociated with poor survival[187], and that strong staining of RAD50/MRE11/NBS1 wasassociated with a favorable survival[188]. Both TGFBR2 and BAX have clearly importantfunctions in the cell as they regulate TGF- signaling (see page 33) and apoptosis,respectively. Even though their involvement in tumorigenesis is obvious, the potential todiscriminate those with good and poor prognosis is more uncertain. TGFBR2 is one of themost frequently mutated genes in MSI-tumors as it is mutated in 96% of right-sided tumors(Paper IV). This will make it impossible to divide a group in two as all tumors have the samealteration. Therefore, the discrimination achieved when comparing survival in those with andwithout TGFBR2 mutations are likely to be caused by a difference in tumor location. BAX isalso more frequently mutated in right-sided tumors, although not significant. Therefore onecan not exclude that survival differences associated to BAX mutations are due to locationrather than mutations as well.In order to maximize the likelihood of including driver-genes that are likely to have animpact on tumorigenesis and therefore also in discriminating survival, certain selectioncriteria were employed in Paper IV. Figure 15 shows the size of our study (Paper IV)compared to other studies analyzing coding repetitive units in MSI-tumors. We identifiedmutations in RCC2 to be associated with improved prognosis in two independent tumorseries of the MSI phenotype. The RCC2 protein is involved in the segregation of57