Patterns of gene promoter methylation in squamous cell cancer of the head and neck

Oncogene. 2002 Jun 20;21(27):4231-6. doi: 10.1038/sj.onc.1205528.


Promoter methylation is an important pathway in transcriptional silencing of known and candidate tumor suppressor genes in Head and Neck Squamous Cell Carcinoma (HNSCC). In order to study the association of tumor suppressor gene promoter methylation in HNSCC with patient clinical characteristics, especially alcohol consumption and tobacco smoking, we examined promoter methylation of the p16(INK4a), DAP-kinase, E-Cadherin, and RASSF1A genes using methylation-specific PCR (MSP) in 80 patients. The prevalence of p16(INK4a), DAP-kinase, E-Cadherin, and RASSF1A promoter methylation was 26/80 (32.5%), 19/80 (23.8%), 29/80 (36.3%), 6/80 (7.5%) respectively. In 48 cases (60%), at least one of these promoters was methylated. There was a significant association of methylation of any of these genes and ever smoking (P=0.006). p16(INK4a) gene promoter methylation was associated with a younger age of smoking initiation (P<0.03); E-Cadherin promoter methylation was associated with an increased number of pack years smoked (P<0.03). We also found an association of methylation of any gene and T status (OR=2.7, P<0.05). Tumors with p16(INK4a) methylation were significantly less likely to show lymph node metastasis (P<0.001). DAP-kinase promoter methylation was significantly associated with lymph node metastasis and this relationship was dependent upon p16(INK4a) promoter methylation status. Our results suggest that, in HNSCC, promoter methylation of these four genes accumulates with increasing tumor size. This may reflect distinct pathways of somatic inactivation leading to cancer; additional larger studies are needed to further investigate this possibility. Tobacco smoking may play an important role in both the occurrence of promoter methylation as well as delineating the precise pathway that eventually results in a tumorigenic phenotype.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Aged
  • Alcohol Drinking / genetics
  • Apoptosis Regulatory Proteins
  • Cadherins / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Carcinoma, Squamous Cell / complications
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / pathology
  • Cell Transformation, Neoplastic / genetics
  • DNA Methylation*
  • DNA, Neoplasm / chemistry
  • DNA, Neoplasm / genetics
  • Death-Associated Protein Kinases
  • Disease Progression
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Gene Silencing
  • Genes, Tumor Suppressor*
  • Genes, p16
  • Head and Neck Neoplasms / complications
  • Head and Neck Neoplasms / genetics*
  • Head and Neck Neoplasms / pathology
  • Humans
  • Lymphatic Metastasis / genetics
  • Male
  • Middle Aged
  • Neoplasm Proteins / genetics*
  • Promoter Regions, Genetic*
  • Smoking / genetics
  • Time Factors
  • Tumor Suppressor Proteins*


  • Apoptosis Regulatory Proteins
  • Cadherins
  • DNA, Neoplasm
  • Neoplasm Proteins
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • Death-Associated Protein Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases