Abstract
The molecular basis of aberrant protein glycosylation, a pathological alteration widespread in colorectal cancers (CRC), and the mechanisms by which it contributes to tumor progression remain largely unknown. We performed targeted re-sequencing of 430 glycosylation-associated genes in a series of patient-derived CRC cell lines (N = 31) and matched primary tumor tissues, identifying 12 new significantly mutated glycosylation-associated genes in colon cancer. 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 recurrent mutations within these genes in colon and other gastrointestinal cancers. Systematic biochemical and phenotypic characterization of the candidate wild-type and mutant glycosyltransferases demonstrated these mutations as either markedly altering protein localization, post-translational modification, encoded enzymatic activities and/or the migratory potential of colon carcinoma cells. These findings 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.
Highlights
Core 1,3, O-linked glycan biosynthesis protein N- and O-glycosylation are complex processes involving a multitude of enzymes, we initiated a study to characterize the extent and significance of genetic defects in the colon cancer glycome
Biochemical, and functional approaches in a series of patient-derived colon cancer cell lines and matched primary tumors, we identified significant molecular and functional defects in 3 genes that likely control the biosynthesis of N- and Core 1–3 O-linked glycans expressed in the colon, uncovering mechanisms potentially contributing to aberrant glycosylation and colon tumor progression
We performed targeted re-sequencing of 430 glycosylation genes in a set of patient-derived microsatellite stable (MSS) CRC cell lines (N = 31) (Supplementary Tables S1–S3) to determine the type and extent of glycosylation pathway defects in colon cancer, and to assess for the prevalence of bi-allelic defects in these glycosylation pathway genes
Summary
Core 1,3, O-linked glycan biosynthesis protein N- and O-glycosylation are complex processes involving a multitude of enzymes, we initiated a study to characterize the extent and significance of genetic defects in the colon cancer glycome. Biochemical, and functional approaches in a series of patient-derived colon cancer cell lines and matched primary tumors, we identified significant molecular and functional defects in 3 genes that likely control the biosynthesis (termination and elongation) of N- and Core 1–3 O-linked glycans expressed in the colon, uncovering mechanisms potentially contributing to aberrant glycosylation and colon tumor progression
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