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

Pauline M.W. van Kempen, Liselotte van Bockel, Weibel W. Braunius, Cathy B. Moelans, Marina van Olst, Rick de Jong, Inge Stegeman, Paul J. van Diest, Wilko Grolman, Stefan M. Willems

Research output: Contribution to journalArticlepeer-review

Abstract

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. HPV-positive and HPV-negative oropharynx squamous cell carcinoma show distinct biological and clinical features. Our study further underscores this diversity by illustrating that HPV-positive and HPV-negative oropharyngeal squamous cell carcinoma (OPSCCs) also differ epigenetically.

Original languageEnglish (US)
Pages (from-to)1185-1196
Number of pages12
JournalCancer medicine
Volume3
Issue number5
DOIs
StatePublished - Oct 1 2014

Keywords

  • CADM1
  • CHFR
  • HPV
  • Hypermethylation
  • Oropharynx squamous cell carcinoma
  • TIMP3

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Cancer Research

Fingerprint Dive into the research topics of 'HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation'. Together they form a unique fingerprint.

Cite this