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

DNA错配修复缺陷是约15%的散发性结直肠癌、子宫内膜癌和胃癌的特征，并导致被称为微卫星的重复序列元件突变的快速积累。如果这种不稳定性影响到位于基因编码序列中的微卫星，那么由此产生的移码突变就会产生移码突变转录本，这些转录本要么会被无义介导的RNA衰变（NMD）系统降解，要么会编码部分或完全丧失正常功能的截断蛋白。一些MSI靶基因的移码突变预计会导致与MSI肿瘤相关的独特临床组织病理学和生物学特征。如果这些受影响的蛋白质参与了细胞大分子的修饰，cMS的不稳定性预计会导致细胞结构的特异性改变。特别是，由糖基转移酶和糖苷酶的复杂框架严格控制的蛋白质和鞘脂的糖基化构成了大量潜在的msi特异性表位。在目前的提案中，我们的目标是确定编码碳水化合物识别机制蛋白质的基因的cMS移码突变谱，重点是糖基转移酶，糖苷酶和凝集素，并表征mmr缺陷肿瘤细胞的异常糖基化特征。这些ms特异性糖标记可能是开发新的诊断工具或治疗策略的关键靶点。

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.