Novel O-glycosylation Gene Mutations in Colon Cancer

描述（由申请人提供）：我是凯斯西储大学综合癌症中心医学系的研究讲师。我的主要导师是桑福德·马科维茨博士我的短期目标是在癌症糖基化研究的拟议领域获得必要的理论和技术技能，我的长期目标是进行有关癌症易感性和进展的分子方面的转化研究。本提案的长期目标是鉴定和确定O-糖基化途径缺陷在结肠肿瘤发病机制中的作用。蛋白质糖基化是参与多种细胞过程的基本机制。异常糖基化是几种人类癌症的标志，已被认为对细胞稳态过程具有深远影响。然而，迄今为止，异常糖基化的潜在分子基础及其在肿瘤发生过程中的作用仍然在很大程度上未知。最近，我发现了失活的生殖细胞和体细胞突变的基因编码N-乙酰半乳糖胺转移酶12（GALNT 12），催化启动步骤粘蛋白型O-糖基化，在个人与结肠癌。这些发现提供了结肠癌中O-糖基化途径存在遗传缺陷的第一个证据，并表明结肠癌和其他癌症中常见的异常糖基化在某些情况下可能代表由糖基转移酶基因突变引起的主要异常，并直接导致癌症表型。该提议的主要目标是，a）检查结肠癌中编码参与O-聚糖生物合成的酶的另外的O-糖基化途径基因中突变的存在，B）确定GALNT 12和其它O-糖基化基因的双等位基因失活是否是结肠肿瘤发展所必需的，c）开发小鼠模型以确定GALNT 12的缺失是否增强对结肠癌发生的易感性，和d）采用蛋白质组学技术鉴定在结肠肿瘤发展中起作用的GALNT 12的内源性蛋白质靶。作为我职业发展计划的一部分，我将接受糖生物学，蛋白质组学和遗传流行病学领域的必要教学培训。沿着我的共同导师托马斯格肯博士和罗伯特埃尔斯顿博士，马科维茨博士和他的小组将为我提供一个出色的研究和教育环境，这将有助于推进我成为癌症糖基化研究的独立研究者的目标。 公共卫生相关性：异常蛋白质糖基化是一种广泛存在于包括结肠癌在内的几种人类癌症中的病理学改变，并且通常伴随疾病的发作和进展。目前的研究计划旨在确定异常糖基化的分子基础及其在结肠肿瘤发展中的作用。这反过来将大大有助于设计更好的预防和针对性治疗结肠癌的策略。

DESCRIPTION (provided by applicant): I am a Research Instructor in the Department of Medicine at the Case Western Reserve University Comprehensive Cancer Center. My primary mentor is Dr. Sanford Markowitz. My short-term objectives are to gain the necessary theoretical and technical skills in the proposed area of cancer glycosylation research, and my long-term goal is to conduct translational research pertaining to the molecular aspects of cancer predisposition and progression. The long range objectives of this proposal are to identify and determine the role of O-glycosylation pathway defects in the pathogenesis of colon neoplasia. Protein glycosylation is a fundamental mechanism involved in multiple cellular processes. Aberrant glycosylation is a hallmark of several human cancers that has been suggested to have a profound effect on the cellular homeostatic processes. To date, the underlying molecular basis of aberrant glycosylation and its role in the tumorigenic process however remains largely unknown. Recently, I discovered inactivating germline and somatic mutations in the gene encoding for N-acetylgalactosaminyl transferase12 (GALNT12), which catalyzes the initiating step in mucin type O-glycosylation, in individuals with colon cancer. These findings provide the first evidence for the presence of genetic defects in the O-glycosylation pathway in colon cancers, and suggest that aberrant glycosylation commonly seen in colon and other cancers may in some instances represent a primary abnormality resulting from mutations in glycosyltransferase genes, and directly contributing to the cancer phenotype. The major goals of this proposal are, a) to examine colon cancers for the presence of mutations in additional O-glycosylation pathway genes that encode for enzymes involved in O-glycan biosynthesis, b) to determine whether bi-allelic inactivation of GALNT12 and other O-glycosylation genes is essential for colon tumor development, c) to develop mouse models to determine if loss of GALNT12 enhances the susceptibility to colon carcinogenesis, and d) to employ proteomic techniques to identify endogenous protein targets of GALNT12 that play a role in colon tumor development. As part of my career development plan, I will undergo the necessary didactic training in the field(s) of glycobiology, proteomics and genetic epidemiology. Along with my co-mentors Dr. Thomas Gerken and Dr. Robert Elston, Dr. Markowitz and his group will provide me with an outstanding research and educational environment that will help in advancing my goal of becoming an independent investigator in cancer glycosylation research. PUBLIC HEALTH RELEVANCE: Aberrant protein glycosylation is a pathological alteration that is wide-spread in several types of human cancers including colon cancer, and usually accompanies the onset and progression of the disease. The current research proposal is designed to identify the molecular basis of aberrant glycosylation and its role in tumor development within the colon. This in turn will significantly aid in designing better prevention and targeted treatment strategies for colon cancer.