title: HPV DNA, E6*I-mRNA expression and p16INK4A immunohistochemistry in head and neck cancer - how valid is p16INK4A as surrogate marker?
abstract: It has been proposed that p16(INK4A) qualifies as a surrogate marker for viral oncogene activity in head and neck cancer (HNSCC). By analyzing 78 HNSCC we sought to validate the accuracy of p16(INK4A) as a reliable marker of active HPV infections in HNSCC. To this end we determined HPV DNA (HPVD) and E6*I mRNA (HPVR) expression status and correlated these results with p16(INK4A) staining. In tonsillar SCC 12/20 were HPVD+ and 12/12 of these showed active HPV infections whereas in non-tonsillar SCC 10/58 were HPVD+ and 5/10 showed active HPV infections. Thus, we prove about 8% of non-tonsillar SCC to be also correlated with HPV-associated carcinogenesis. Strikingly, 3/14 (21.4%) of tonsillar and non-tonsillar HPVD+/HPVR+ cases did not show p16(INK4A) overexpression and these cases would have been missed when applying initial p16(INK4A) staining only. However, in 13 cases negative for HPV, DNA p16(INK4A) was overexpressed. In conclusion, our data confirm tonsillar SCC to be predominantly but not only associated with active HPV infections. Furthermore, our data show that p16(INK4A) overexpression is not evident in a subgroup of HNSCC with active HPV infection. Definitive HPV data should therefore be utilized in diagnostics and treatment modalities of HPV positive and HPV negative HNSCC patients, resulting in a paradigm shift regarding these obviously different tumor entities.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, House 27, 24105 Kiel, Germany. Electronic address: mhoffmann@hno.uni-kiel.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Hoffmann
authors.affiliation: Department of Radiation Oncology, University Medical Center Hamburg-Eppendorf, D-Martinistr. 52, 20246 Hamburg, Germany.
authors.forename: Silke
authors.initials: S
authors.lastname: Tribius
authors.affiliation: Department of Prosthodontics, Propaedeutics and Dental Materials, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany; Institute of Immunology, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany.
authors.forename: Elgar Susanne
authors.initials: ES
authors.lastname: Quabius
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, House 27, 24105 Kiel, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Henry
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, House 27, 24105 Kiel, Germany.
authors.forename: Saskia
authors.initials: S
authors.lastname: Pfannenschmidt
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, House 27, 24105 Kiel, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Burkhardt
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, House 27, 24105 Kiel, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Görögh
authors.affiliation: German Cancer Research Center (DKFZ), Infection and Cancer Program (F020), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Gordana
authors.initials: G
authors.lastname: Halec
authors.affiliation: Department of Otorhinolaryngology, University of Schleswig-Holstein, Campus Luebeck, Ratzeburger Allee 160, D-23538 Luebeck, Germany.
authors.forename: Anna Sophie
authors.initials: AS
authors.lastname: Hoffmann
authors.affiliation: Expert Team Life Sciences, Deutsche Bank AG, Große Gallusstr. 10-14, D-60311 Frankfurt, Germany.
authors.forename: Tomas
authors.initials: T
authors.lastname: Kahn
authors.affiliation: Institute for Pathology, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
authors.affiliation: Institute for Pathology, Christian-Albrechts-University Kiel, Arnold-Heller-Straße 3, 24105 Kiel, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Haag
authors.affiliation: German Cancer Research Center (DKFZ), Infection and Cancer Program (F020), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Tim
authors.initials: T
authors.lastname: Waterboer
authors.affiliation: German Cancer Research Center (DKFZ), Infection and Cancer Program (F020), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Schmitt
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000821:virology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis*; D004279:DNA, Viral / Q000032:analysis*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D060885:Multiplex Polymerase Chain Reaction; D009856:Oncogene Proteins, Viral / Q000032:analysis*; D030361:Papillomavirus Infections / Q000150:complications / Q000175:diagnosis; D012333:RNA, Messenger / Q000032:analysis; D000077195:Squamous Cell Carcinoma of Head and Neck; D014067:Tonsillar Neoplasms / Q000378:metabolism / Q000821:virology
chemical_list: D015415:Biomarkers; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; C466080:E6 protein, human papillomavirus type 1; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger