TY - JOUR
T1 - Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers
AU - Guda, Kishore
AU - Moinova, Helen
AU - He, Jian
AU - Jamison, Oliver
AU - Ravi, Lakshmeswari
AU - Natale, Leanna
AU - Lutterbaugh, James
AU - Lawrence, Earl
AU - Lewis, Susan
AU - Willson, James K.V.
AU - Lowe, John B.
AU - Wiesner, Georgia L.
AU - Parmigiani, Giovanni
AU - Barnholtz-Sloan, Jill
AU - Dawson, Dawn W.
AU - Velculescu, Victor E.
AU - Kinzler, Kenneth W.
AU - Papadopoulos, Nikolas
AU - Vogelstein, Bert
AU - Willis, Joseph
AU - Gerken, Thomas A.
AU - Markowitz, Sanford D.
PY - 2009/8/4
Y1 - 2009/8/4
N2 - 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 identi-fied 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.
AB - 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 identi-fied 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.
KW - Cancer
KW - GALNT
KW - Glycosylation
UR - http://www.scopus.com/inward/record.url?scp=69149083658&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=69149083658&partnerID=8YFLogxK
U2 - 10.1073/pnas.0901454106
DO - 10.1073/pnas.0901454106
M3 - Article
C2 - 19617566
AN - SCOPUS:69149083658
SN - 0027-8424
VL - 106
SP - 12921
EP - 12925
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 31
ER -