Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers.
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.
Guda
Kishore
K
Department of Medicine, Case Western Reserve University and Case Medical Center, Cleveland, OH 44106, USA.
Moinova
Helen
H
He
Jian
J
Jamison
Oliver
O
Ravi
Lakshmeswari
L
Natale
Leanna
L
Lutterbaugh
James
J
Lawrence
Earl
E
Lewis
Susan
S
Willson
James K V
JK
Lowe
John B
JB
Wiesner
Georgia L
GL
Parmigiani
Giovanni
G
Barnholtz-Sloan
Jill
J
Dawson
Dawn W
DW
Velculescu
Victor E
VE
Kinzler
Kenneth W
KW
Papadopoulos
Nikolas
N
Vogelstein
Bert
B
Willis
Joseph
J
Gerken
Thomas A
TA
Markowitz
Sanford D
SD
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
C465011:GALNT12 protein, human; D017350:N-Acetylgalactosaminyltransferases