Abstract
BACKGROUND: The loss of E-cadherin (ECAD) protein expression has been linked to aggressive head and neck squamous cell carcinoma (HNSCC). Promoter hypermethylation of the cadherin 1, type 1 (CDH1) gene (encoding ECAD) is 1 mechanism by which this protein can be inactivated, although this epigenetic alteration of the gene has not been linked conclusively to poorer patient outcome and, in fact, may be associated with better patient prognosis. METHODS: The authors investigated the prevalence of CDH1 promoter hypermethylation in a population-based case series of 340 primary HNSCC tumors using methylation-specific polymerase chain reaction. They also studied the association between CDH1 hypermethylation and patient demographic characteristics using multivariate analysis and examined the impact of CDH1 hypermethylation on patient survival using both univariate and multivariate methods. RESULTS: Hypermethylation of CDH1 was significantly more prevalent (P < .03) among individuals with a low smoking history independent of whether they were seropositive for human papillomavirus type 16 (HPV-16). Patients who had tumors with CDH1 hypermethylation had significantly better overall survival compared with patients who had tumors without hypermethylation (P < .02; log-rank test). This effect was independent of HPV-16 status and demonstrated a significant hazard ratio of 0.5 (95% confidence interval, 0.3-0.9) in a model that controlled for HPV-16 serology, age, sex, and tumor stage. CONCLUSIONS: The current results suggested that hypermethylation of CDH1 occurs more commonly in patients with HNSCC who are low smokers, suggesting that an additional factor may be driving this epigenetic alteration. Clinically, CDH1 hypermethylation may hold powerful prognostic potential in addition to that observed with HPV serology, and the authors concluded that it should be pursued in additional studies.