NDLI: Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers

Content Provider	PubMed Central
Author	Guda, Kishore Helen, Moinova He, Jian Jamison, Oliver Ravi, Lakshmeswari Natale, Leanna James, Lutterbaugh Lawrence, Earl Lewis, Susan Willson, James K. V. Lowe, John B. Wiesner, Georgia L. Giovanni, Parmigiani Jill, Barnholtz-sloan Dawson, Dawn W. Velculescu, Victor E. Kinzler, Kenneth W. Papadopoulos, Nikolas Vogelstein, Bert Willis, Joseph Gerken, Thomas A. Markowitz, Sanford D.
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.
Related Links	http://dx.doi.org/10.1073/pnas.0901454106
Ending Page	12925
Page Count	5
Starting Page	12921
File Format	PDF
ISSN	00278424
e-ISSN	10916490
Journal	Proceedings of the National Academy of Sciences of the United States of America
Issue Number	31
Volume Number	106
Language	English
Publisher	National Academy of Sciences
Publisher Date	2009-08-04
Access Restriction	Open
Rights Holder	National Academy of Sciences
Subject Keyword	General Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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