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

The test series included a low number of MSI-H rectal tumors which differed from thetraditional right-sided MSI-tumors in mutation load, both on the individual gene mutationlevel as well as the total mutation level, as the rectal tumors had significantly fewermutations. From developmental biology we know that the large intestine originates from twodifferent embryological regions, the midgut and the hindgut, of which the midgut becomesthe small intestines and proximal part of the large bowel, while the hindgut constitutes thelast third of transversum and extends to the anal opening. Also, the environmentalconditions in the colon differ, both the content and the passage time of the feces, makingthe exposure of potential mutagens different in the different regions. This difference inbiology may explain the discrepancy in the downstream mutation targets. As previouslymentioned, sporadic MSI-tumors are generally caused by hypermethylation of MLH1. In aprevious study we analyzed MLH1 hypermethylation for most of the samples includedhere[32]. As expected, we found that the majority of right-sided tumors had hypermethylatedMLH1 promoters. In contrast, none of the rectal tumors had this feature, indicating thatMSI is caused by mechanisms other than MLH1 methylation in these tumors. Bias fromhereditary cancer, especially Lynch’s syndrome has been excluded, as assessed by writtenquestionnaires.[31]RCC2 as a target for frameshift mutation in MSI-cancers was identified by a systematicdatabase search in 2002 (reported using its alias KIAA1470).[33] However, this is the firsttime the mutation status of the gene is linked to survival. In this study we show that indels ina coding mononucleotide repeat in RCC2 were significantly associated with improvedsurvival both in the hypothesis generating and the hypothesis testing cancer series.21