Aberrant promoter hypermethylation of multiple genes in head and neck squamous cell carcinoma.
OBJECTIVE
Epigenetic alteration, via promoter hypermethylation, inactivates genes important for the development of head and neck squamous cell carcinoma (SCCHN). The aim of this study is to characterize and correlate, with clinical parameters, the promoter methylation profile of DNA repair genes, hMLH1 and O6-methylguanine-DNA methyltransferase (MGMT), and tumor-suppressor gene p16.


METHODS
Fifty-one cases of SCCHN, collected from the paraffin block archives (1997-1999) in the Department of Pathology at the University of Arkansas for medical sciences, provided DNA for methylation-specific PCR using primers specific for hMLH1, MGMT, and p16.


RESULTS
Sixty-two percent displayed promoter hypermethylation in at least one gene, with 23% seen for hMLH1, 30% for MGMT, and 36% for p16. Promoter hypermethylation of these genes separately or in combination was not associated with history of smoking and alcohol use, tumor size, nodal status, clinical stage, and overall survival. Promoter hypermethylation of more than 1 gene was significantly associated with increased 2-year disease-free survival. The probability of surviving 2 years without tumor recurrence was 100% with promoter hypermethylation in 2 or 3 genes and 46% with promoter hypermethylation in none or just 1 gene (P=.013). Promoter hypermethylation of 2 or 3 genes was independently related to increased 2-year cumulative disease-free survival (P=.028).


CONCLUSIONS
Promoter hypermethylation of hMLH1, MGMT, and p16 genes was commonly detected in 47 SCCHN cases with up to 65% showing aberrant promoter hypermethylation in at least 1 gene. Promoter hypermethylation of 2 or 3 genes was significantly associated with increased 2-year disease-free survival, suggesting that promoter hypermethylation of multiple genes might improve survival. Significant correlation was also noted between a positive alcohol use history and promoter hypermethylation of the MGMT gene with no promoter hypermethylation of the p16 gene.
Puri
Sajeev K
SK
Department of Otolaryngology-Head and Neck Surgery, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA. purisajeevk@uams.edu
Si
Lingbao
L
Fan
Chun-Yang
CY
Hanna
Ehab
E
D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002352:Carrier Proteins; D019175:DNA Methylation; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D019942:Genes, p16 / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1