title: Biochemical and functional characterization of glycosylation-associated mutational landscapes in colon cancer.
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.
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Srividya
authors.initials: S
authors.lastname: Venkitachalam
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Leslie
authors.initials: L
authors.lastname: Revoredo
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.|Division of General-Medical Sciences-Oncology, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Vinay
authors.initials: V
authors.lastname: Varadan
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Fecteau
authors.affiliation: Division of Hematology and Oncology, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Lakshmeswari
authors.initials: L
authors.lastname: Ravi
authors.affiliation: Division of Hematology and Oncology, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: James
authors.initials: J
authors.lastname: Lutterbaugh
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.|Division of Hematology and Oncology, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.|Department of Pathology, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Willis
authors.affiliation: Department of Chemistry, Case Western Reserve University, Cleveland OH 44106, U.S.A.|Department of Pediatrics, Case Western Reserve University, Cleveland OH 44106, U.S.A.|Department of Biochemistry, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gerken
authors.affiliation: Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland OH 44106, U.S.A.|Division of General-Medical Sciences-Oncology, Case Western Reserve University, Cleveland OH 44106, U.S.A.
authors.forename: Kishore
authors.initials: K
authors.lastname: Guda
mesh_terms: D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods*; D005700:Galactosyltransferases / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D016695:Glycosyltransferases / Q000235:genetics*; D006801:Humans; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics*; D011134:Polysaccharides / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational; D012799:Sialyltransferases / Q000235:genetics*
chemical_list: D011134:Polysaccharides; D016695:Glycosyltransferases; C000613740:B4GALT2 protein, human; D005700:Galactosyltransferases; D017351:N-Acetylglucosaminyltransferases; C428132:B3GNT2 protein, human; C000613741:ST6GALNAC2 protein, human; D012799:Sialyltransferases