Novel O-glycosylation Gene Mutations in Colon Cancer

个人描述(申请人提供)：我是凯斯西储大学综合癌症中心医学部的一名研究导师。我的主要导师是桑福德·马科维茨博士。我的短期目标是在拟议的癌症糖基化研究领域获得必要的理论和技术技能，长期目标是进行与癌症易感性和进展的分子方面有关的翻译研究。这项建议的长期目标是识别和确定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，已被认为对细胞内环境平衡过程有深远影响。然而，到目前为止，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在很大程度上仍不清楚。最近，我发现在结肠癌患者中，编码N-乙酰半乳糖胺转移酶12(GALNT12)的基因发生了种系和体细胞突变，GALNT12催化粘蛋白O-糖基化的起始步骤。这些发现首次证明在结肠癌中存在O-糖基化途径的遗传缺陷，并表明在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是由于糖基转移酶基因突变而导致的原发异常，并直接导致癌症表型。该建议的主要目标是：a)检查结肠癌是否存在额外的O-糖基化途径基因的突变，这些基因编码参与O-糖链生物合成的酶的突变；b)确定GALNT12和其他O-糖基化基因的双等位失活是否对结肠癌的发生至关重要；c)建立小鼠模型，以确定GALNT12的缺失是否增加了结肠癌发生的易感性；以及d)使用蛋白质组学技术来确定GALNT12的内源性蛋白靶点在结肠癌的发生中发挥了作用。作为我职业发展计划的一部分，我将在糖生物学、蛋白质组学和遗传流行病学领域接受必要的授课培训(S)。与我的共同导师Thomas Gerken博士和Robert Elston博士一起，Markowitz博士和他的团队将为我提供一个出色的研究和教育环境，这将有助于我实现成为癌症糖基化研究的独立研究员的目标。 公共卫生相关性：异常蛋白糖基化是一种病理改变，广泛存在于包括结肠癌在内的几种人类癌症中，通常伴随着疾病的发生和发展。目前的研究方案旨在确定异常糖基化的分子基础及其在结肠内肿瘤发展中的作用。这反过来将大大有助于设计更好的结肠癌预防和有针对性的治疗策略。

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.