Positive correlation of tissue inhibitor of metalloproteinase-3 and death-associated protein kinase hypermethylation in head and neck squamous cell carcinoma

Chetan S. Nayak, André Lopes Carvalho, Carmen Jeronimo, Rui Henrique, Michael M. Kim, Mohammad O. Hoque, Steve Chang, Wei Wen Jiang, Wayne Koch, William Westra, David Sidransky, Joseph Califano

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

OBJECTIVES/HYPOTHESIS: 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. STUDY DESIGN: 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. CONCLUSION: TIMP-3 promoter hypermethylation is elevated in HNSCC and is highly correlated with DAPK hypermethylation, implying a functional relationship between these genes.

Original languageEnglish (US)
Pages (from-to)1376-1380
Number of pages5
JournalLaryngoscope
Volume117
Issue number8
DOIs
StatePublished - Aug 1 2007

Keywords

  • DAP kinase
  • Head and neck squamous cell carcinoma
  • Hypermethylation
  • Quantitative PCR
  • TIMP-3
  • Tumor suppressor gene

ASJC Scopus subject areas

  • Otorhinolaryngology

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    Nayak, C. S., Carvalho, A. L., Jeronimo, C., Henrique, R., Kim, M. M., Hoque, M. O., Chang, S., Jiang, W. W., Koch, W., Westra, W., Sidransky, D., & Califano, J. (2007). Positive correlation of tissue inhibitor of metalloproteinase-3 and death-associated protein kinase hypermethylation in head and neck squamous cell carcinoma. Laryngoscope, 117(8), 1376-1380. https://doi.org/10.1097/MLG.0b013e31806865a8