Document Detail


Aberrant p16((INK4a)) methylation is a frequent event in colorectal cancers: prognostic value and relation to mRNA expression and immunoreactivity.
MedLine Citation:
PMID:  19779933     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Aberrant p16((INK4a)) promoter methylation is common in colorectal cancer (CRC), but its clinicopathological significance remains controversial. The present study was therefore conducted to analyze p16((INK4a)) methylation and its relationship to clinicopathological features, mRNA levels and immunoreactivity in a series of lesions. METHODS: p16((INK4a)) methylation was assessed for normal mucosa (n = 30) and CRC samples (n = 212) by methylation-specific real-time quantitative PCR, and p16((INK4a)) expression by immunostaining in formalin-fixed paraffin-embedded specimens. In addition, fresh DNA (n = 61) was analyzed for relationships to p16((INK4a)) mRNA by reverse-transcription PCR. RESULTS: The p16((INK4a)) methylation index of normal mucosa samples ranged from 0 to 2% (mean, 0.23%; median, 0.02%), while the values for tumor samples varied widely from 0 to 100% (mean, 25.7%; median, 7.1%), the difference being statistically significant (P < 0.001). Of 151 paraffin-embedded CRC tissue samples, 51 (34%), 54 (36%), and 46 (30%) were classified as low, intermediate, and high for aberrant methylation of p16((INK4a)). High p16((INK4a)) methylation was significantly associated with large tumor size (P = 0.025). Patients with higher methylation further showed more frequent recurrence as compared with the low-methylation group, and shortened cancer-related survival (Hazard ratio [HR], 3.379; P < 0.001) and recurrence-free survival (HR, 3.962; P < 0.001 on multivariate analysis). A significant inverse relationship was apparent between the p16((INK4a)) methylation and immunoreactivity (P = 0.017). A similar tendency was also observed for the methylation status and the mRNA level (P = 0.195). CONCLUSIONS: We conclude that p16((INK4a)) methylation results in transcriptional silencing and defines a group of CRCs with a poor prognosis.
Authors:
Hiroyuki Mitomi; Naoshi Fukui; Nobuho Tanaka; Hideki Kanazawa; Tsuyoshi Saito; Takashi Matsuoka; Takashi Yao
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of cancer research and clinical oncology     Volume:  136     ISSN:  1432-1335     ISO Abbreviation:  J. Cancer Res. Clin. Oncol.     Publication Date:  2010 Feb 
Date Detail:
Created Date:  2009-12-30     Completed Date:  2010-01-18     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7902060     Medline TA:  J Cancer Res Clin Oncol     Country:  Germany    
Other Details:
Languages:  eng     Pagination:  323-31     Citation Subset:  IM    
Affiliation:
Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. hmitomi@juntendo.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Aged, 80 and over
Chemotherapy, Adjuvant
Colorectal Neoplasms / genetics*,  pathology*,  therapy
Cyclin-Dependent Kinase Inhibitor p16 / genetics*
DNA Methylation*
Disease-Free Survival
Female
Humans
Immunohistochemistry
Male
Middle Aged
Multivariate Analysis
Neoplasm Staging
Odds Ratio
Polymerase Chain Reaction / methods
Predictive Value of Tests
Prognosis
Promoter Regions, Genetic
Reverse Transcriptase Polymerase Chain Reaction
Chemical
Reg. No./Substance:
0/Cyclin-Dependent Kinase Inhibitor p16

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