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Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers.

Publication ,  Journal Article
Goel, A; Arnold, CN; Niedzwiecki, D; Carethers, JM; Dowell, JM; Wasserman, L; Compton, C; Mayer, RJ; Bertagnolli, MM; Boland, CR
Published in: Cancer Res
May 1, 2004

Loss of PTEN tumor suppressor function is observed in tumors of breast, prostate, thyroid, and endometrial origin. Allelic losses in the proximity of the PTEN locus (10q23) also occur in sporadic colorectal cancers (CRCs), but biallelic inactivation of this site has not been frequently demonstrated. We hypothesized that alternative mechanisms of PTEN allelic inactivation, such as promoter hypermethylation, might be operative in CRC and that PTEN inactivation may be related to recognized forms of genomic instability. We characterized a cohort of 273 sporadic CRCs by determining their microsatellite instability (MSI) status. Of these, 146 cancers were examined for PTEN promoter methylation by methylation-specific PCR. Mutations at the poly(A)6 repeat sequences in PTEN exons 7 and 8 and deletions at the 10q23 locus were also identified using microsatellite analysis. The presence of PTEN protein was determined by immunostaining, and the results were correlated with the promoter methylation status. We observed that PTEN promoter hypermethylation was a frequent occurrence in MSI-high (MSI-H) tumors (19.1% of MSI-H versus 2.2% of MSI-low/microsatellite stable tumors; P = 0.002). A PTEN mutation or a deletion event was present in 60% of the tumors with promoter region hypermethylation. Hypermethylation of the PTEN promoter correlated significantly with either decreased or complete loss of PTEN protein expression (P = 0.004). This is the first demonstration of PTEN inactivation as a result of promoter hypermethylation in MSI-H sporadic CRCs. These data suggest that this silencing mechanism plays a major role in PTEN inactivation and, in colon cancer, may be more important than either allelic losses or inactivating mutations. The significant correlation of PTEN hypermethylation with MSI-H tumors further suggests that PTEN is an additional important "target" of methylation along with the hMLH1 gene in the evolution of MSI-H CRCs and also confers the "second hit" in the biallelic inactivation mechanism for some proportion of tumors.

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Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

May 1, 2004

Volume

64

Issue

9

Start / End Page

3014 / 3021

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Promoter Regions, Genetic
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Mutation
  • Middle Aged
  • Microsatellite Repeats
  • Male
  • Loss of Heterozygosity
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Goel, A., Arnold, C. N., Niedzwiecki, D., Carethers, J. M., Dowell, J. M., Wasserman, L., … Boland, C. R. (2004). Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res, 64(9), 3014–3021. https://doi.org/10.1158/0008-5472.can-2401-2
Goel, Ajay, Christian N. Arnold, Donna Niedzwiecki, John M. Carethers, Jeannette M. Dowell, Linda Wasserman, Carolyn Compton, Robert J. Mayer, Monica M. Bertagnolli, and C Richard Boland. “Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers.Cancer Res 64, no. 9 (May 1, 2004): 3014–21. https://doi.org/10.1158/0008-5472.can-2401-2.
Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, et al. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004 May 1;64(9):3014–21.
Goel, Ajay, et al. “Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers.Cancer Res, vol. 64, no. 9, May 2004, pp. 3014–21. Pubmed, doi:10.1158/0008-5472.can-2401-2.
Goel A, Arnold CN, Niedzwiecki D, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR. Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers. Cancer Res. 2004 May 1;64(9):3014–3021.

Published In

Cancer Res

DOI

ISSN

0008-5472

Publication Date

May 1, 2004

Volume

64

Issue

9

Start / End Page

3014 / 3021

Location

United States

Related Subject Headings

  • Tumor Suppressor Proteins
  • Promoter Regions, Genetic
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • Oncology & Carcinogenesis
  • Mutation
  • Middle Aged
  • Microsatellite Repeats
  • Male
  • Loss of Heterozygosity