title: HPV-related methylation signature predicts survival in oropharyngeal squamous cell carcinomas.
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.
authors: Department of Otolaryngology, Head and Neck Surgery, University Hospital Heidelberg, Heidelberg, Germany.
authors: Efterpi
authors: E
authors: Kostareli
authors: Dana
authors: D
authors: Holzinger
authors: Olga
authors: O
authors: Bogatyrova
authors: Thomas
authors: T
authors: Hielscher
authors: Gunnar
authors: G
authors: Wichmann
authors: Michaela
authors: M
authors: Keck
authors: Bernd
authors: B
authors: Lahrmann
authors: Niels
authors: N
authors: Grabe
authors: Christa
authors: C
authors: Flechtenmacher
authors: Christopher R
authors: CR
authors: Schmidt
authors: Tanguy
authors: T
authors: Seiwert
authors: Gerhard
authors: G
authors: Dyckhoff
authors: Andreas
authors: A
authors: Dietz
authors: Daniela
authors: D
authors: Höfler
authors: Michael
authors: M
authors: Pawlita
authors: Axel
authors: A
authors: Benner
authors: Franz X
authors: FX
authors: Bosch
authors: Peter
authors: P
authors: Plinkert
authors: Christoph
authors: C
authors: Plass
authors: Dieter
authors: D
authors: Weichenhan
authors: Jochen
authors: J
authors: Hess
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000821:virology; D016022:Case-Control Studies; D018899:CpG Islands; D019175:DNA Methylation; D018572:Disease-Free Survival; D050991:GATA4 Transcription Factor / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D018398:Homeodomain Proteins / Q000235:genetics; D054884:Host-Pathogen Interactions; D052162:Human papillomavirus 16 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D020411:Oligonucleotide Array Sequence Analysis; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000821:virology; D030361:Papillomavirus Infections / Q000235:genetics* / Q000401:mortality / Q000821:virology; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D018091:Receptors, AMPA / Q000235:genetics; D050697:Retinal Dehydrogenase / Q000235:genetics; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D059467:Transcriptome
chemical_list: D050991:GATA4 Transcription Factor; C484170:GATA4 protein, human; D018398:Homeodomain Proteins; C485533:IRX4 protein, human; C486680:OSR2 protein, human; D018091:Receptors, AMPA; D014157:Transcription Factors; C104724:glutamate receptor ionotropic, AMPA 4; D000080924:Aldehyde Dehydrogenase 1 Family; C545372:ALDH1A2 protein, human; D050697:Retinal Dehydrogenase
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