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

Kishore Guda, Helen Moinova, Jian He, Oliver Jamison, Lakshmeswari Ravi, Leanna Natale, James Lutterbaugh, Earl Lawrence, Susan Lewis, James K V Willson, John B. Lowe, Georgia L. Wiesner, Giovanni Parmigiani, Jill Barnholtz-Sloan, Dawn W. Dawson, Victor E. Velculescu, Kenneth W. Kinzler, Nikolas Papadopoulos, Bert Vogelstein, Joseph WillisThomas A. Gerken, Sanford D. Markowitz

Research output: Contribution to journalArticle

91 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)12921-12925
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number31
DOIs
StatePublished - Aug 4 2009

Fingerprint

N-Acetylgalactosaminyltransferases
Germ-Line Mutation
Colonic Neoplasms
Glycosylation
Mutation
Germ Cells
Neoplasms
Mucins
Mutation Rate
Microsatellite Repeats
Genes
Disease Progression
polypeptide N-acetylgalactosaminyltransferase
Colon
Enzymes

Keywords

  • Cancer
  • GALNT
  • Glycosylation

ASJC Scopus subject areas

  • General

Cite this

Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. / Guda, Kishore; Moinova, Helen; He, Jian; Jamison, Oliver; Ravi, Lakshmeswari; Natale, Leanna; Lutterbaugh, James; Lawrence, Earl; Lewis, Susan; Willson, James K V; Lowe, John B.; Wiesner, Georgia L.; Parmigiani, Giovanni; Barnholtz-Sloan, Jill; Dawson, Dawn W.; Velculescu, Victor E.; Kinzler, Kenneth W.; Papadopoulos, Nikolas; Vogelstein, Bert; Willis, Joseph; Gerken, Thomas A.; Markowitz, Sanford D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 31, 04.08.2009, p. 12921-12925.

Research output: Contribution to journalArticle

Guda, K, Moinova, H, He, J, Jamison, O, Ravi, L, Natale, L, Lutterbaugh, J, Lawrence, E, Lewis, S, Willson, JKV, Lowe, JB, Wiesner, GL, Parmigiani, G, Barnholtz-Sloan, J, Dawson, DW, Velculescu, VE, Kinzler, KW, Papadopoulos, N, Vogelstein, B, Willis, J, Gerken, TA & Markowitz, SD 2009, 'Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 31, pp. 12921-12925. https://doi.org/10.1073/pnas.0901454106
Guda, Kishore ; Moinova, Helen ; He, Jian ; Jamison, Oliver ; Ravi, Lakshmeswari ; Natale, Leanna ; Lutterbaugh, James ; Lawrence, Earl ; Lewis, Susan ; Willson, James K V ; Lowe, John B. ; Wiesner, Georgia L. ; Parmigiani, Giovanni ; Barnholtz-Sloan, Jill ; Dawson, Dawn W. ; Velculescu, Victor E. ; Kinzler, Kenneth W. ; Papadopoulos, Nikolas ; Vogelstein, Bert ; Willis, Joseph ; Gerken, Thomas A. ; Markowitz, Sanford D. / Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 31. pp. 12921-12925.
@article{a05c7cde96b4448e8a3874a10cccaf2c,
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 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.",
keywords = "Cancer, GALNT, Glycosylation",
author = "Kishore Guda and Helen Moinova and Jian He and Oliver Jamison and Lakshmeswari Ravi and Leanna Natale and James Lutterbaugh and Earl Lawrence and Susan Lewis and Willson, {James K V} and Lowe, {John B.} and Wiesner, {Georgia L.} and Giovanni Parmigiani and Jill Barnholtz-Sloan and Dawson, {Dawn W.} and Velculescu, {Victor E.} and Kinzler, {Kenneth W.} and Nikolas Papadopoulos and Bert Vogelstein and Joseph Willis and Gerken, {Thomas A.} and Markowitz, {Sanford D.}",
year = "2009",
month = "8",
day = "4",
doi = "10.1073/pnas.0901454106",
language = "English (US)",
volume = "106",
pages = "12921--12925",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "31",

}

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

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

SN - 0027-8424

IS - 31

ER -