title: Comparative analysis of transcriptomics based hypoxia signatures in head- and neck squamous cell carcinoma.
abstract: OBJECTIVE
  Hypoxia renders tumors resistant to radiotherapy. However, the paucity of sensitive and reliable methods for detection of tumor hypoxia limits the translation of novel therapy strategies targeting this well-known resistance factor. We sought to investigate the ability of three previously discovered transcriptomics based hypoxia signatures to identify hypoxic tumors and consequently discriminate between patients with poor- vs. good prognosis.
  
  
  METHODS
  Three different hypoxia gene signatures developed by Toustrup et al., Eustace et al. and Lendahl et al. were evaluated in an independent cohort consisting of 302 patients with head and neck squamous cell carcinoma (HNSCC). Clinical data as well as genome-wide RNA-sequencing based gene expression data were retrieved from The Cancer Genome Atlas (TCGA). Clustering and statistical analysis were performed using Statistical Utilities for Microarray and Omics data (SUMO) software package.
  
  
  RESULTS
  The 15 gene hypoxia signature developed by Toustrup et al. as well as the 30 gene signature by Lendahl et al. successfully discriminated between HNSCC patients with poor vs. good prognosis. The 26 gene signature developed by Eustace et al. was prognostic in HNSCC patients treated with radiotherapy. The best prognostic value was achieved when a consensus cohort of patients was assigned, i.e., low- or high- degree of tumor hypoxia was found, by all three signatures. Interestingly, the number of signature genes could be successfully reduced to the only common gene across all three signatures, i.e., P4HA1, encoding prolyl-4-hydroxylase, alpha polypeptide I.
  
  
  CONCLUSIONS
  This is the first independent proof for the feasibility of hypoxia gene expression signatures as a prognostic tool in HNSCC patients.
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Germany.
authors.forename: Bouchra
authors.initials: B
authors.lastname: Tawk
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Schwager
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Deffaa
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Dyckhoff
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Germany; Division of Neurosurgical Research, Department of Neurosurgery, University of Heidelberg, Germany.
authors.forename: Rolf
authors.initials: R
authors.lastname: Warta
authors.affiliation: German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Germany.
authors.forename: Annett
authors.initials: A
authors.lastname: Linge
authors.affiliation: German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Wilko
authors.initials: W
authors.lastname: Weichert
authors.affiliation: German Cancer Consortium (DKTK), Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Radiation Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; OncoRay - National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Helmholtz-Zentrum Dresden - Rossendorf, Institute of Radiooncology, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, University of Heidelberg, Germany.
authors.forename: Christel
authors.initials: C
authors.lastname: Herold-Mende
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Debus
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany; Molecular & Translational Radiation Oncology, Heidelberg Ion Therapy Center (HIT), Heidelberg Institute of Radiation Oncology (HIRO), University of Heidelberg Medical School and National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Germany. Electronic address: a.amir@dkfz.de.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
mesh_terms: D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D015687:Cell Hypoxia / Q000235:genetics*; D005240:Feasibility Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D052138:Genes, Neoplasm; D006258:Head and Neck Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis; D059467:Transcriptome; D016896:Treatment Outcome
keywords: Gene signatures; Head and neck squamous cell carcinoma; Hypoxia; Transcriptomics