Cited by 302Genetic factors in colorectal cancerEpigenetics and DNA MethylationColorectal Cancer Treatments and Studies

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Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers

Goel, Ajay, Arnold, Christian N., Niedzwiecki, Donna, Carethers, John M., Dowell, Jeannette M., Wasserman, Linda, Compton, Carolyn, Mayer, Robert J., Bertagnolli, Monica M., Boland, C. Richard·2004·Cancer Research

DOI 10.1158/0008-5472.can-2401-2

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Abstract

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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Authors: Goel, A., Arnold, C. N., Niedzwiecki, D., Carethers, J. M., Dowell, J. M., Wasserman, L., Compton, C., Mayer, R. J., Bertagnolli, M. M., & Boland, C. R.
Affiliations: University of California San Diego (US)
Duke University (US)
McGill University (CA)
Dana-Farber Cancer Institute (US)
Brigham and Women's Hospital (US)
United States Department of Veterans Affairs (US)
ORCID: Goel, Ajay
Arnold, Christian N.
Niedzwiecki, Donna
Carethers, John M.
Compton, Carolyn
Mayer, Robert J.
Bertagnolli, Monica M.
Boland, C. Richard
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2004-05-01
Volume: 64
Issue: 9
Pages: 3014-3021
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-2401-2
OpenAlex: W2054894450
Cited by: 302
References: 35
Citations by year: 2026: 2 · 2025: 3 · 2024: 8 · 2023: 12 · 2022: 9 · 2021: 11 · 2020: 12 · 2019: 12 · 2018: 13 · 2017: 5 · 2016: 12 · 2015: 19 · 2014: 17 · 2013: 27 · 2012: 30
FWCI: 10.72
Type: journal article
Language: en
Open access: closed
Locations: Cancer Research (publishedVersion)
PubMed (publishedVersion)
FreiDok plus (Universitätsbibliothek Freiburg) (submittedVersion)
Funders: University of California, San Diego
National Cancer Institute (R01-CA-72851, R01CA072851, R01 CA90231, R01CA090231, U10CA031946, CA-31946)
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
Keywords: PTEN, promoter hypermethylation, microsatellite instability, sporadic colorectal cancer, tumor suppressor inactivation, PTEN mutation, PTEN protein expression, genomic instability, second hit, DNA methylation
MeSH terms: Aged, Alleles, Chromosomes, Human, Pair 10, Female, Humans, Male, Middle Aged, Mutation, Phosphoric Monoester Hydrolases, Promoter Regions, Genetic, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Microsatellite Repeats, DNA Methylation, Loss of Heterozygosity, Gene Silencing, Tumor Suppressor Proteins, PTEN Phosphohydrolase

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Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers

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