HPV‐positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation

Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV) in a proportion of tumors. HPV‐positive OPSCC is considered a distinct molecular entity with a prognostic advantage compared to HPV‐negative cases. Silencing of cancer‐related genes by DNA promoter hypermethylation may play an important role in the development of OPSCC. Hence, we examined promoter methylation status in 24 common tumor suppressor genes in a group of 200 OPSCCs to determine differentially methylated genes in HPV‐positive versus HPV‐negative primary OPSCC. Methylation status was correlated with HPV status, clinical features, and patient survival using multivariate methods. Additionally, methylation status of 16 cervical squamous cell carcinomas (SCC) was compared with HPV‐positive OPSCC. Using methylation‐specific probe amplification, HPV‐positive OPSCC showed a significantly higher cumulative methylation index (CMI) compared to HPV‐negative OPSCC (P=0.008). For the genes CDH13, DAPK1, and RARB, both HPV‐positive and HPV‐negative OPSCC showed promoter hypermethylation in at least 20% of the tumors. HPV status was found to be an independent predictor of promoter hypermethylation of CADM1 (P