Scientists Identify Three Glycosyltransferases as Significant Mutational Targets in Colon Cancer

Little is known about the molecular basis of aberrant protein glycosylation, a complex enzymatic process that is a hallmark of many human cancers including colorectal cancers (CRC), and how it may contribute to tumor progression. In a new study published in Scientific Reports, an online journal of the Nature Publishing Group, scientists at Case Western Reserve University School of Medicine have successfully characterized the mutational landscapes of glycosylation-associated genes in colon cancer, identifying three glycosyltransferases as significant mutational targets in CRC.

These findings are significant as they strongly suggest that functionally deleterious mutations in glycosyltransferase genes in part underlie aberrant glycosylation, and contribute to the pathogenesis of molecular subsets of colon and other gastrointestinal malignancies. The study, “Biochemical and functional characterization of glycosylation associated mutational landscapes in colon cancer,” can be accessed here

Kishore Guda, DVM, PhD, assistant professor of general medical sciences (oncology) at the School of Medicine, led this critical research, involving the targeted re-sequencing of 430 glycosylation-associated genes and matched primary tumor tissues. Through this process, Guda and his team identified three glycosyltransferases (B3GNT2, B4GALT2, ST6GALNAC2) as significant mutational targets in CRCs. Analysis of independent large-scale tumor tissue datasets confirmed recurrent mutations within these genes in colon and other gastrointestinal cancers. The study lays important groundwork for the future characterization of these glycosyltransferases that may provide additional insights into the biologic role of these genes in colon cancer progression.

"With so many questions surrounding the potential role of aberrant glycosylation in tumor progression, we were excited to conduct this research that builds on our previous findings of mutations in the gene encoding for the enzyme GALNT12 in a subset of colon cancer cases,” said Dr. Guda. “Our findings demonstrate that these mutant glycosyltransferases have a significant impact on the encoded enzymatic activity and/or the migratory potential of colon carcinoma cells, and set up future research that can further explore their role in tumor progression.”

A team of Case Western scientists collaborated on this paper: Srividya Venkitachalam, PhD; Leslie Revoredo, PhD; Vinay Varadan, PhD; Ryan E. Fecteau, PhD; Lakshmeswari Ravi; James Lutterbaugh; Sanford D. Markowitz, MD, PhD; Joseph E. Willis; Thomas A. Gerken; and Kishore Guda, DVM, PhD. Other contributors include Martina Veigl, PhD, and Simone Edelheit at the CWRU Genomics Core; Mike Sramkoski at the Cytometry and Imaging Core; and Daniela Schlatzer at the CWRU Center for Proteomics and Bioinformatics.

Research was generously supported by PHS awards: K08 CA148980 (K.G.); Case GI SPORE P50 CA150964 (V.V., S.D.M., J.E.W., K.G.); P30 CA043703 (V.V., S.D.M., J.E.W., K.G.); U54 CA163060 (V.V., S.D.M., J.E.W., K.G.); R01 CA078834 (T.A.G.) and U01 GM113534 (T.A.G).

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Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.

Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."

The School of Medicine is affiliated with University Hospitals Cleveland Medical Center, MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002.

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