Frequent Inactivation of PTEN by Promoter Hypermethylation in Microsatellite Instability-High Sporadic Colorectal Cancers
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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Loss of function of PTEN occurs in 30% of sporadic colorectal cancers.
“Loss of function of PTEN, which antagonizes PI3K activity, occurs in 30 % of sporadic CRCs through a variety of mechanisms [73, 74].”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [74]
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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
- Venue
- Cancer Research
- Published
- 2004-05-01
- Volume
- 64
- Issue
- 9
- Pages
- 3014-3021
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- 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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