Analysis of coding microsatellite frameshift mutations in MSI-H colorectal carcinomas and characterization of their effects on the cellular glycosylation machinery

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Deficient DNA mismatch repair is a hallmark of about 15 % of sporadic colorectal, endometrial and gastric cancers and results in rapid accumulation of mutations in repetitive sequence elements termed microsatellites. If this instability affects microsatellites located in gene coding sequences, the resulting frameshift mutations give rise of frameshift mutant transcripts that either might be degraded by the nonsense mediated RNA decay (NMD) system or encode truncated proteins with partial or complete loss of normal function. Frameshift mutations in some of these MSI target genes are expected to contribute to the distinct clinico-histopathological and biological features associated with MSI tumors. If such affected proteins are involved in the modification of cellular macromolecules, cMS instability is expected to lead to specifically altered cellular structures. In particular, glycosylation of proteins and sphingolipids which is tightly controlled by a complex framework of glycosyltransferases and glycosidases constitute a a large pool of potential MSI-specific epitopes. In the current proposal we aim to determine the cMS frameshift mutation profile of genes encoding proteins of the carbohydrate recognition machinery with emphasis on glycosyltransferases, glycosidases and lectins and characterize resulting aberrant glycosylation signatures of MMR-deficient tumor cells. These MSIspecific glyco-signatures might represent key targets for the development of novel diagnostic tools or therapeutic strategies.