1. HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas
- Author
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Michael Pawlita, Dieter Weichenhan, Michaela K. Keck, Efterpi Kostareli, Niels Grabe, Thomas Hielscher, Christa Flechtenmacher, Bernd Lahrmann, Andreas Dietz, Gunnar Wichmann, Jochen Hess, Christopher R. Schmidt, Daniela Höfler, Axel Benner, Peter K. Plinkert, Christoph Plass, Olga Bogatyrova, Tanguy Y. Seiwert, Dana Holzinger, Franz X. Bosch, and Gerhard Dyckhoff
- Subjects
Candidate gene ,Kaplan-Meier Estimate ,Biology ,Aldehyde Dehydrogenase 1 Family ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Receptors, AMPA ,Promoter Regions, Genetic ,030304 developmental biology ,Oligonucleotide Array Sequence Analysis ,Proportional Hazards Models ,Regulation of gene expression ,Homeodomain Proteins ,0303 health sciences ,Human papillomavirus 16 ,Tissue microarray ,Papillomavirus Infections ,Retinal Dehydrogenase ,Promoter ,General Medicine ,Methylation ,Sequence Analysis, DNA ,DNA Methylation ,Molecular biology ,3. Good health ,GATA4 Transcription Factor ,Gene Expression Regulation, Neoplastic ,Oropharyngeal Neoplasms ,Differentially methylated regions ,CpG site ,030220 oncology & carcinogenesis ,Case-Control Studies ,DNA methylation ,Host-Pathogen Interactions ,Cancer research ,Carcinoma, Squamous Cell ,CpG Islands ,Transcriptome ,Research Article ,HeLa Cells ,Transcription Factors - Abstract
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.
- Published
- 2013