title: Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers.
abstract: Aberrant glycosylation is a pathological alteration that is widespread in colon cancer, and usually accompanies the onset and progression of the disease. To date, the molecular mechanisms underlying aberrant glycosylation remain largely unknown. In this study, we identify somatic and germ-line mutations in the gene encoding for polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) in individuals with colon cancer. Biochemical analyses demonstrate that each of the 8 GALNT12 mutations identified inactivates the normal function of the GALNT enzyme in initiating mucin type O-linked protein glycosylation. Two of these inactivating GALNT12 mutations were identified as acquired somatic mutations in a set of 30 microsatellite stable colon tumors. Relative to background gene mutation rates, finding these somatic GALNT12 mutations was statistically significant at P < 0.001. Six additional inactivating GALNT12 mutations were detected as germ-line changes carried by patients with colon cancer; however, no inactivating variants were detected among cancer-free controls (P = 0.005). Notably, in 3 of the 6 individuals harboring inactivating germ-line GALNT12 mutations, both a colon cancer and a second independent epithelial cancer had developed. These findings suggest that genetic defects in the O-glycosylation pathway in part underlie aberrant glycosylation in colon cancers, and they contribute to the development of a subset of these malignancies.
authors.affiliation: Department of Medicine, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
authors.forename: Kishore
authors.initials: K
authors.lastname: Guda
authors.forename: Helen
authors.initials: H
authors.lastname: Moinova
authors.forename: Jian
authors.initials: J
authors.lastname: He
authors.forename: Oliver
authors.initials: O
authors.lastname: Jamison
authors.forename: Lakshmeswari
authors.initials: L
authors.lastname: Ravi
authors.forename: Leanna
authors.initials: L
authors.lastname: Natale
authors.forename: James
authors.initials: J
authors.lastname: Lutterbaugh
authors.forename: Earl
authors.initials: E
authors.lastname: Lawrence
authors.forename: Susan
authors.initials: S
authors.lastname: Lewis
authors.forename: James K V
authors.initials: JK
authors.lastname: Willson
authors.forename: John B
authors.initials: JB
authors.lastname: Lowe
authors.forename: Georgia L
authors.initials: GL
authors.lastname: Wiesner
authors.forename: Giovanni
authors.initials: G
authors.lastname: Parmigiani
authors.forename: Jill
authors.initials: J
authors.lastname: Barnholtz-Sloan
authors.forename: Dawn W
authors.initials: DW
authors.lastname: Dawson
authors.forename: Victor E
authors.initials: VE
authors.lastname: Velculescu
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Nikolas
authors.initials: N
authors.lastname: Papadopoulos
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
authors.forename: Joseph
authors.initials: J
authors.lastname: Willis
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Gerken
authors.forename: Sanford D
authors.initials: SD
authors.lastname: Markowitz
mesh_terms: D000368:Aged; D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics*; D018095:Germ-Line Mutation; D006031:Glycosylation; D006801:Humans; D051379:Mice; D009154:Mutation; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D041681:NIH 3T3 Cells
chemical_list: C465011:GALNT12 protein, human; D017350:N-Acetylgalactosaminyltransferases