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


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.

DOI: 10.1172/JCI67010

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@article{Kostareli2013HPVrelatedMS, title={HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas.}, author={Efterpi Kostareli and Dana Holzinger and Olga Bogatyrova and Thomas Hielscher and Gunnar Wichmann and Michaela K. Keck and B. Lahrmann and Niels Grabe and Christa Flechtenmacher and Christopher Roman Schmidt and Tanguy Y. Seiwert and Gerhard Dyckhoff and Andreas Dietz and Daniela H{\"{o}fler and Michael Pawlita and Axel Benner and Franz X. Bosch and Peter K. Plinkert and Christoph Plass and Dieter Weichenhan and Jochen Hess}, journal={The Journal of clinical investigation}, year={2013}, volume={123 6}, pages={2488-501} }