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

had mutation frequencies of 75% or higher in both series. TAF1B is an essential part of theRNA polymerase I cofactor SL1, which is important for transcriptional initiation in general,as it is involved in the binding of regulatory proteins at the TATA-box.[27;28] Its comutatedgene, ACVR2A (activin receptor 2), transmits the growth inhibitory effects ofactivin via phosphorylation of SMAD proteins to affect gene transcription through theTGF signaling pathway.[29] Activin has been shown to regulate differentiation,proliferation and apoptosis in several cancer types.[29] When both these genes areinactivated in a tumor, it provides severe deregulation of transcription as a whole as well asloss of the growth inhibitory effects of activin,[29] strategies which are positive for a tumorcell.MRE11A is involved in double strand DNA break repair along with several other proteinsand is clearly important in maintaining high DNA fidelity.[30] The role of ASTE1(previously known as HT001) is not known, so any mutational consequences of this generemain to be resolved. Hence, the impact of the loss of both these genes in a tumor cell thusremains elusive. Another possibility is that the recognized correlations are merely due to highmutation rates rather than important biological functions.MSI-L tumors are usually acknowledged to have a phenotype analogous to MSS.[6;31] Asexpected, we saw a significant difference in mutation frequencies between tumors with ahigh and low degree of microsatellite instability as the MSI-L tumors harbored a mean ofone mutation per tumor. This indicates that MSI-L is insufficient to induce the mutatorphenotype in CRC.20