Linked Life Data

15126336

Source:http://linkedlifedata.com/resource/pubmed/id/15126336

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
9
pubmed:dateCreated
2004-5-5
pubmed:abstractText
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.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
May
pubmed:issn
0008-5472
pubmed:author
pubmed:issnType
Print
pubmed:day
1
pubmed:volume
64
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
3014-21
pubmed:dateRevised
2011-9-22
pubmed:meshHeading
pubmed-meshheading:15126336-Aged, pubmed-meshheading:15126336-Alleles, pubmed-meshheading:15126336-Chromosomes, Human, Pair 10, pubmed-meshheading:15126336-Colorectal Neoplasms, pubmed-meshheading:15126336-DNA Methylation, pubmed-meshheading:15126336-Female, pubmed-meshheading:15126336-Gene Expression Regulation, Neoplastic, pubmed-meshheading:15126336-Gene Silencing, pubmed-meshheading:15126336-Humans, pubmed-meshheading:15126336-Loss of Heterozygosity, pubmed-meshheading:15126336-Male, pubmed-meshheading:15126336-Microsatellite Repeats, pubmed-meshheading:15126336-Middle Aged, pubmed-meshheading:15126336-Mutation, pubmed-meshheading:15126336-PTEN Phosphohydrolase, pubmed-meshheading:15126336-Phosphoric Monoester Hydrolases, pubmed-meshheading:15126336-Promoter Regions, Genetic, pubmed-meshheading:15126336-Tumor Suppressor Proteins
pubmed:year
2004
pubmed:articleTitle
Frequent inactivation of PTEN by promoter hypermethylation in microsatellite instability-high sporadic colorectal cancers.
pubmed:affiliation
Department of Medicine and Comprehensive Cancer Center, University of California San Diego, La Jolla, California, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't