title: The role of HPV RNA transcription, immune response-related gene expression and disruptive TP53 mutations in diagnostic and prognostic profiling of head and neck cancer.
abstract: Stratification of head and neck squamous cell carcinomas (HNSCC) based on HPV16 DNA and RNA status, gene expression patterns, and mutated candidate genes may facilitate patient treatment decision. We characterize head and neck squamous cell carcinomas (HNSCC) with different HPV16 DNA and RNA (E6*I) status from 290 consecutively recruited patients by gene expression profiling and targeted sequencing of 50 genes. We show that tumors with transcriptionally inactive HPV16 (DNA+ RNA-) are similar to HPV-negative (DNA-) tumors regarding gene expression and frequency of TP53 mutations (47%, 8/17 and 43%, 72/167, respectively). We also find that an immune response-related gene expression cluster is associated with lymph node metastasis, independent of HPV16 status and that disruptive TP53 mutations are associated with lymph node metastasis in HPV16 DNA- tumors. We validate each of these associations in another large data set. Four gene expression clusters which we identify differ moderately but significantly in overall survival. Our findings underscore the importance of measuring the HPV16 RNA (E6*I) and TP53-mutation status for patient stratification and identify associations of an immune response-related gene expression cluster and TP53 mutations with lymph node metastasis in HNSCC.
authors.affiliation: Clinic for Otorhinolaryngology, University Hospital Leipzig, Liebigstr. 10-14, 04103, Leipzig, Germany.|LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Gunnar
authors.initials: G
authors.lastname: Wichmann
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Maciej
authors.initials: M
authors.lastname: Rosolowski
authors.affiliation: Faculty of Medicine, Interdisciplinary Center for Clinical Research, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Knut
authors.initials: K
authors.lastname: Krohn
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kreuz
authors.affiliation: Clinic for Otorhinolaryngology, University Hospital Leipzig, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Boehm
authors.affiliation: Clinic for Otorhinolaryngology, University Hospital Leipzig, Liebigstr. 10-14, 04103, Leipzig, Germany.
authors.forename: Anett
authors.initials: A
authors.lastname: Reiche
authors.affiliation: Clinic for Otorhinolaryngology, University Hospital Leipzig, Liebigstr. 10-14, 04103, Leipzig, Germany.|LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Scharrer
authors.affiliation: Clinic for Maxillofacial Surgery, University Hospital Leipzig, 04103, Leipzig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Halama
authors.affiliation: Institute of Pathology, University Hospital Leipzig, 04103, Leipzig, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Bertolini
authors.affiliation: Institute of Pathology, University Hospital Leipzig, 04103, Leipzig, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Bauer
authors.affiliation: Division of Genome Modifications and Carcinogenesis (F020), Infection and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69121, Heidelberg, Germany.
authors.forename: Dana
authors.initials: D
authors.lastname: Holzinger
authors.affiliation: Division of Genome Modifications and Carcinogenesis (F020), Infection and Cancer Program, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69121, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Pawlita
authors.affiliation: Research Group Molecular Mechanisms of Head and Neck Tumors, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Section Experimental and Translational Head and Neck Oncology, Department of Otolaryngology, Head and Neck Surgery University Heidelberg, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hess
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Engel
authors.affiliation: Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Hasenclever
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Scholz
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Ahnert
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Kirsten
authors.affiliation: Clinic for Maxillofacial Surgery, University Hospital Leipzig, 04103, Leipzig, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hemprich
authors.affiliation: Institute of Pathology, University Hospital Leipzig, 04103, Leipzig, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Wittekind
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Faculty of Medicine, Institute of Environmental Medicine and Hygiene, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Olf
authors.initials: O
authors.lastname: Herbarth
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute of Clinical Immunology and Transfusion Medicine, University Hospital, 04103, Leipzig, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Horn
authors.affiliation: Clinic for Otorhinolaryngology, University Hospital Leipzig, Liebigstr. 10-14, 04103, Leipzig, Germany.|LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dietz
authors.affiliation: LIFE-Leipzig Research Center for Civilization Diseases, University of Leipzig, 04103, Leipzig, Germany.|Institute for Medical Informatics, Statistics and Epidemiology (IMISE), University of Leipzig, 04107, Leipzig, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Loeffler
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000276:immunology / Q000401:mortality / Q000556:secondary / Q000821:virology*; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D005787:Gene Frequency; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000401:mortality / Q000473:pathology / Q000821:virology*; D052162:Human papillomavirus 16 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D008207:Lymphatic Metastasis; D009154:Mutation; D030361:Papillomavirus Infections / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D012367:RNA, Viral / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D012367:RNA, Viral; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
keywords: APC; TP53; consensus clustering; gene expression; head and neck squamous cell carcinoma; human papillomavirus; neck metastasis