Positive correlation of tissue inhibitor of metalloproteinase-3 and death-associated protein kinase hypermethylation in head and neck squamous cell carcinoma.
OBJECTIVE
Promoter hypermethylation of tumor suppressor genes is common in head and neck cancer as well as other primary cancers resulting in epigenetic gene silencing. Tissue inhibitor of metalloproteinase-3 (TIMP-3) has been shown to have promoter hypermethylation in several solid tumors, but has not been identified in head and neck squamous cell carcinoma (HNSCC). Our objective was to determine if TIMP-3 promoter was hypermethylated in HNSCC, if there was any correlation with death associated protein kinase (DAPK), a tumor suppressor whose promoter has been hypermethylated at high levels in HNSCC, and if any clinical factors influence hypermethylation of either of these genes.


METHODS
Prospective study.


METHODS
Tumor samples from 124 patients with HNSCC were evaluated for promoter hypermethylation for TIMP-3 and DAPK using quantitative methylation specific polymerase chain reaction (qMSP). We compared both TIMP-3 and DAPK hypermethylation in HNSCC with each other as well as with other clinical variables.


RESULTS
We found that TIMP-3 was hypermethylated in approximately 71.8% of the tumor samples and DAPK was hypermethylated in 74.2%. The presence of TIMP-3 and DAPK promoter hypermethylation was significantly higher than in control specimens. More importantly, TIMP-3 and DAPK hypermethylations in these samples were highly correlated with a concordance of 78% (P < .001). DAPK was also correlated with current alcohol consumption (P < .028), but neither TIMP-3 nor DAPK hypermethylation was significantly correlated with other clinical variables or with survival.


CONCLUSIONS
TIMP-3 promoter hypermethylation is elevated in HNSCC and is highly correlated with DAPK hypermethylation, implying a functional relationship between these genes.
Nayak
Chetan S
CS
Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287-0910, USA.
Carvalho
André Lopes
AL
Jeronimo
Carmen
C
Henrique
Rui
R
Kim
Michael M
MM
Hoque
Mohammad O
MO
Chang
Steve
S
Jiang
Wei-Wen
WW
Koch
Wayne
W
Westra
William
W
Sidransky
David
D
Califano
Joseph
J
D000368:Aged; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004273:DNA, Neoplasm / Q000235:genetics*; D064550:Death-Associated Protein Kinases; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011401:Promoter Regions, Genetic; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics* / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; D019717:Tissue Inhibitor of Metalloproteinase-3; D008780:Methyltransferases; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases