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.
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.
|Evans, Daniel R; Venkitachalam, Srividya; Revoredo, Leslie et al. (2018) Evidence for GALNT12 as a moderate penetrance gene for colorectal cancer. Hum Mutat 39:1092-1101|
|Venkitachalam, Srividya; Guda, Kishore (2017) Altered glycosyltransferases in colorectal cancer. Expert Rev Gastroenterol Hepatol 11:5-7|
|Fecteau, Ryan E; Kong, Jianping; Kresak, Adam et al. (2016) Association Between Germline Mutation in VSIG10L and Familial Barrett Neoplasia. JAMA Oncol 2:1333-1339|
|Blum, Andrew E; Venkitachalam, Srividya; Guo, Yan et al. (2016) RNA Sequencing Identifies Transcriptionally Viable Gene Fusions in Esophageal Adenocarcinomas. Cancer Res 76:5628-5633|
|Venkitachalam, Srividya; Revoredo, Leslie; Varadan, Vinay et al. (2016) Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer. Sci Rep 6:23642|
|Sun, Xiangqing; Elston, Robert; Falk, Gary W et al. (2016) Linkage and related analyses of Barrett's esophagus and its associated adenocarcinomas. Mol Genet Genomic Med 4:407-19|
|Guda, Kishore; Veigl, Martina L; Varadan, Vinay et al. (2015) Novel recurrently mutated genes in African American colon cancers. Proc Natl Acad Sci U S A 112:1149-54|
|Varadan, Vinay; Singh, Salendra; Nosrati, Arman et al. (2015) ENVE: a novel computational framework characterizes copy-number mutational landscapes in colorectal cancers from African American patients. Genome Med 7:69|
|Fecteau, Ryan E; Lutterbaugh, James; Markowitz, Sanford D et al. (2014) GNAS mutations identify a set of right-sided, RAS mutant, villous colon cancers. PLoS One 9:e87966|
|Guda, Kishore; Fink, Stephen P; Milne, Ginger L et al. (2014) Inactivating mutation in the prostaglandin transporter gene, SLCO2A1, associated with familial digital clubbing, colon neoplasia, and NSAID resistance. Cancer Prev Res (Phila) 7:805-12|
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