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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 < 0.001), CHFR (P = 0.027), and TIMP3 (P < 0.001). CADM1 and CHFR showed similar methylation patterns in OPSCC and cervical SCC, but TIMP3 showed no methylation in cervical SCC in contrast to OPSCC. Methylation status of neither individual gene nor CMI was associated with survival. These results suggest that HPV-positive tumors are to a greater extent driven by promotor hypermethylation in these tumor suppressor genes. Especially CADM1 and TIMP3 are significantly more frequently hypermethylated in HPV-positive OPSCC and CHFR in HPV-negative tumors.

Objectives: Although TP53 mutations in head and neck squamous cell carcinoma (HNSCC) have been extensively studied, their association with the different subsites in the head and neck region has never been described. Methods: Sanger sequence analysis evaluating exons 4-9 in the TP53 gene was performed on 116 HNSCC patients. The exon location, exact codon and corresponding substitution in relation to the anatomical site (subsite) of the HNSCC were evaluated. Results: We found nonsynonymous TP53 mutations in 70% (81/116) of the patients. In oral cavity carcinomas, most mutations occurred in exon 7 (37%). In oropharyngeal and laryngeal tumors, mutations were mainly found in exons 6 and 7. The most common mutation was located in codon 220, and all of these were an Y220C mutation. Five out of nine (56%) Y220C mutations occurred in oropharyngeal tumors. Additionally, 22% of all mutations observed in oropharyngeal squamous cell carcinoma (OPSCC) consisted of Y220C mutations. Conclusion: In this study, the subsite-related distribution of TP53 mutations underlines the biological diversity between tumors arising from different anatomical regions in the head and neck region. Moreover, the Y220C mutation was by far the most prevalent TP53 mutation in HNSCC and a relative hotspot mutation in the oropharynx. (C) 2015 S. Karger AG, Basel