HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas

Efterpi Kostareli, Dana Holzinger, Olga Bogatyrova, Thomas Hielscher, Gunnar Wichmann, Michaela Keck, Bernd Lahrmann, Niels Grabe, Christa Flechtenmacher, Christopher R Schmidt, Tanguy Seiwert, Gerhard Dyckhoff, Andreas Dietz, Daniela Höfler, Michael Pawlita, Axel Benner, Franz X Bosch, Peter Plinkert, Christoph Plass, Dieter WeichenhanJochen Hess

Research output: Contribution to journalArticlepeer-review

85 Citations (Scopus)


High-risk types of human papilloma virus (HPV) are increasingly associated with oropharyngeal squamous cell carcinoma (OPSCC). Strikingly, patients with HPV-positive OPSCC are highly curable with ionizing radiation and have better survival compared with HPV-negative patients, but the underlying molecular mechanisms remain poorly understood. We applied an array-based approach to monitor global changes in CpG island hypermethylation between HPV-negative and HPV-positive OPSCCs and identified a specific pattern of differentially methylated regions that critically depends on the presence of viral transcripts. HPV-related alterations were confirmed for the majority of candidate gene promoters by mass spectrometric, quantitative methylation analysis. There was a significant inverse correlation between promoter hypermethylation of ALDH1A2, OSR2, GATA4, GRIA4, and IRX4 and transcript levels. Interestingly, Kaplan-Meier analysis revealed that a combined promoter methylation pattern of low methylation levels in ALDH1A2 and OSR2 promoters and high methylation levels in GATA4, GRIA4, and IRX4 promoters was significantly correlated with improved survival in 3 independent patient cohorts. ALDH1A2 protein levels, determined by immunohistochemistry on tissue microarrays, confirmed the association with clinical outcome. In summary, our study highlights specific alterations in global gene promoter methylation in HPV-driven OPSCCs and identifies a signature that predicts the clinical outcome in OPSCCs.

Original languageEnglish
Pages (from-to)2488-501
Number of pages14
JournalThe Journal of clinical investigation
Issue number6
Publication statusPublished - Jun 2013
Externally publishedYes


  • Carcinoma, Squamous Cell/genetics
  • Case-Control Studies
  • CpG Islands
  • DNA Methylation
  • Disease-Free Survival
  • GATA4 Transcription Factor/genetics
  • Gene Expression Regulation, Neoplastic
  • HeLa Cells
  • Homeodomain Proteins/genetics
  • Host-Pathogen Interactions
  • Human papillomavirus 16/genetics
  • Humans
  • Kaplan-Meier Estimate
  • Oligonucleotide Array Sequence Analysis
  • Oropharyngeal Neoplasms/genetics
  • Papillomavirus Infections/genetics
  • Promoter Regions, Genetic
  • Proportional Hazards Models
  • Receptors, AMPA/genetics
  • Retinal Dehydrogenase/genetics
  • Sequence Analysis, DNA
  • Transcription Factors/genetics
  • Transcriptome


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