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 p16INK4a, DAP-kinase, E-Cadherin, and RASSF1A genes using methylation-specific PCR (MSP) in 80 patients. The prevalence of p16INK4a, 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). p16INK4a 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 p16INK4a 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 p16INK4a 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.
Bibliographical noteFunding Information:
Supported by: CA78609, ES08357, ES00002 and 1P01-DE12467-05.
- Head and neck cancer
- Oral cancer