Understanding the molecular mechanisms that bring about aberrant protein glycosylation is critical to uncovering the pathways that contribute to overall tumor progression. Little is known about the molecular basis of altered protein glycosylation, which is often the hallmark of many human cancers including colorectal cancers (CRC).
Now, a new study from investigators at Case Western Reserve University (CWRU) School of Medicine has successfully characterized the mutational landscape of glycosylation-associated genes in colon cancer, identifying three glycosyltransferases as significant mutational targets in CRC. Results from this new research 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 findings from this study were published recently in Scientific Reports through an article entitled “Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer.”
The CWRU team analyzed sequencing data from an array of glycosylation-associated genes and matched primary tumor tissues. From their efforts, the scientists were able to identify three glycosyltransferases as significant mutational targets in CRCs.
“We performed targeted re-sequencing of 430 glycosylation-associated genes in a series of patient-derived colorectal cancer (CRC) cell lines (N = 31) and matched primary tumor tissues, identifying 12 new significantly mutated glycosylation-associated genes in colon cancer,” the authors wrote. “In particular, we observed an enrichment of mutations in genes (B3GNT2, B4GALT2, ST6GALNAC2) involved in the biosynthesis of N- and Cores 1–3 O-linked glycans in the colon, accounting for ~16% of the CRCs tested.”
Analysis of independent large-scale tumor tissue datasets confirmed the presence of 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,” stated senior study author Kishore Guda, D.V.M., Ph.D., assistant professor of general medical sciences at CWRU "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."