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

J Clin Invest. 2013 Jun;123(6):2488-501. doi: 10.1172/JCI67010. Epub 2013 May 1.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Carcinoma, Squamous Cell / genetics*
  • Carcinoma, Squamous Cell / mortality
  • Carcinoma, Squamous Cell / virology
  • 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
  • Human papillomavirus 16 / physiology*
  • Humans
  • Kaplan-Meier Estimate
  • Oligonucleotide Array Sequence Analysis
  • Oropharyngeal Neoplasms / genetics*
  • Oropharyngeal Neoplasms / mortality
  • Oropharyngeal Neoplasms / virology
  • Papillomavirus Infections / genetics*
  • Papillomavirus Infections / mortality
  • Papillomavirus Infections / virology
  • Promoter Regions, Genetic
  • Proportional Hazards Models
  • Receptors, AMPA / genetics
  • Retinal Dehydrogenase / genetics
  • Sequence Analysis, DNA
  • Transcription Factors / genetics
  • Transcriptome


  • GATA4 Transcription Factor
  • GATA4 protein, human
  • Homeodomain Proteins
  • IRX4 protein, human
  • OSR2 protein, human
  • Receptors, AMPA
  • Transcription Factors
  • glutamate receptor ionotropic, AMPA 4
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A2 protein, human
  • Retinal Dehydrogenase

Associated data

  • GEO/GSE41152