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

MSI-H 结直肠癌中编码微卫星移码突变的分析及其对细胞糖基化机制影响的表征

• 批准号: 45605061
• 负责人: Professor Dr. Jürgen Kopitz
• 金额: --
• 依托单位: Abteilung für Angewandte Tumorbiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2007
• 资助国家: 德国
• 起止时间: 2006-12-31 至 2010-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/45605061?language=en
• 关键词: Analysis; coding; microsatellite; frameshift; mutations

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.

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标志，并导致称为微卫星的重复序列元件中突变的快速积累。如果这种不稳定性影响位于基因编码序列中的微卫星，则产生的移码突变会产生移码突变转录本，这些转录本可能被无义介导的RNA衰变（NMD）系统降解，或者编码部分或完全丧失正常功能的截短蛋白质。这些MSI靶基因中的一些移码突变预期有助于与MSI肿瘤相关的独特的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细胞大分子的修饰，cMS不稳定性预计会导致细胞结构的特异性改变。特别地，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潜在MSI特异性表位的大库。在目前的建议中，我们的目标是确定cMS移码突变的基因编码的碳水化合物识别机制的蛋白质，重点是糖基转移酶，糖苷酶和凝集素，并表征所产生的异常糖基化的签名MMR缺陷的肿瘤细胞。这些MSI特异性糖特征可能代表开发新型诊断工具或治疗策略的关键目标。