title: Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients.
abstract: Infection with high-risk types of human papilloma virus (HPV) is currently the best-established prognostic marker for head and neck squamous cell carcinoma (HNSCC), one of the most common and lethal human malignancies worldwide. Clinical trials have been launched to address the concept of treatment de-escalation for HPV-positive HNSCC with the final aim to reduce treatment related toxicity and debilitating long-term impacts on the quality of life. However, HPV-related tumors are mainly restricted to oropharyngeal SCC (OPSCC) and there is an urgent need to establish reliable biomarkers for all patients at high risk for treatment failure. A patient cohort (n = 295) with mainly non-OPSCC (72.9%) and a low prevalence of HPV16-related tumors (8.8%) was analyzed by MassARRAY to determine a previously established prognostic methylation score (MS). Kaplan-Meier revealed a highly significant correlation between a high MS and a favorable survival for OPSCC (P = 0.0004) and for non-OPSCC (P<0.0001), which was confirmed for all HNSCC by multivariate Cox regression models (HR: 9.67, 95% CI [4.61-20.30], P<0.0001). Next, we established a minimal methylation signature score (MMSS), which consists of ten most informative of the originally 62 CpG units used for the MS. The prognostic value of the MMSS was confirmed by Kaplan-Meier analysis for all HNSCC (P<0.0001) and non-OPSCC (P = 0.0002), and was supported by multivariate Cox regression models for all HNSCC (HR: 2.15, 95% CI [1.36-3.41], P = 0.001). In summary, the MS and the MMSS exhibit an excellent performance as prognosticators for survival, which is not limited by the anatomical site, and both could be implemented in future clinical trials.
authors.affiliation: a Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany.|b Department of Otolaryngology , Head and Neck Surgery, University Hospital , Heidelberg, Heidelberg , Germany.
authors.forename: Efterpi
authors.initials: E
authors.lastname: Kostareli
authors.affiliation: c Division of Biostatistics, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.affiliation: c Division of Biostatistics, German Cancer Research Center (DKFZ) , Heidelberg , Germany.|d Oslo Center for Biostatistics and Epidemiology, Department of Biostatistics, Institute of Basic Medical Sciences, University of Oslo , Norway.
authors.forename: Manuela
authors.initials: M
authors.lastname: Zucknick
authors.affiliation: e Veneto Institute of Oncology IOV - IRCCS, Immunology and Molecular Oncology Unit , Padua , Italy.|f Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Lorena
authors.initials: L
authors.lastname: Baboci
authors.affiliation: g Department of Otorhinolaryngology , University Hospital Leipzig , Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Wichmann
authors.affiliation: f Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: a Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Mücke
authors.affiliation: f Division of Molecular Diagnostics of Oncogenic Infections, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: e Veneto Institute of Oncology IOV - IRCCS, Immunology and Molecular Oncology Unit , Padua , Italy.
authors.forename: Annarosa
authors.initials: A
authors.lastname: Del Mistro
authors.affiliation: h Department of Neurosciences , ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital , Treviso , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Boscolo-Rizzo
authors.affiliation: h Department of Neurosciences , ENT Clinic and Regional Center for Head and Neck Cancer, University of Padua, School of Medicine, Treviso Regional Hospital , Treviso , Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Da Mosto
authors.affiliation: i Head and Neck Department, Hospital of Cattinara, University of Trieste , Trieste , Italy.
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Tirelli
authors.affiliation: b Department of Otolaryngology , Head and Neck Surgery, University Hospital , Heidelberg, Heidelberg , Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Plinkert
authors.affiliation: g Department of Otorhinolaryngology , University Hospital Leipzig , Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dietz
authors.affiliation: a Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.affiliation: a Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Weichenhan
authors.affiliation: b Department of Otolaryngology , Head and Neck Surgery, University Hospital , Heidelberg, Heidelberg , Germany.|j Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ) , Heidelberg , Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics*; D052162:Human papillomavirus 16; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D000077195:Squamous Cell Carcinoma of Head and Neck
chemical_list: D014408:Biomarkers, Tumor
keywords: DNA methylation; HNSCC; HPV; MassARRAY; OPSCC; head and neck cancer; squamous cell carcinoma