title: Impact of Sonic Hedgehog Pathway Expression on Outcome in HPV Negative Head and Neck Carcinoma Patients after Surgery and Adjuvant Radiotherapy.
abstract: BACKGROUND
  HPV positive patients suffering from head and neck cancer benefit from intensified radiotherapy when applied as a primary as well as an adjuvant treatment strategy. However, HPV negative patients treated with surgery and adjuvant radiotherapy lack validated prognostic biomarkers. It is therefore important to define prognostic biomarkers in this particular patient population. Especially, ´high-risk groups´ need to be defined in order to adapt treatment protocols. Since dysregulation of the sonic hedgehog pathway plays an important role in carcinogenesis, we aimed to assess whether members of the sonic hedgehog-signaling pathway may act as prognostic factors in patients with HPV negative head and neck squamous cell carcinoma.
  
  
  METHODS
  In this prospective study, pretreatment tumor biopsies of patients with head and neck squamous cell carcinoma were taken during panendoscopy (2005 to 2008). All patients were treated with surgery and postoperative radiotherapy. After assessment of HPV and p16 status, protein expression profiles of the Sonic hedgehog-signaling pathway were determined by immunohistochemistry and tissue microarray analyses in 36 HPV negative tumor biopsies. Expression profiles of Sonic hedgehog, Indian hedgehog, Patched, Smoothened, Gli-1, Gli-2 and Gli-3 were correlated with patients´ clinical data, local-control rate, disease-free as well as overall survival. Data from The Cancer Genome Atlas databank were used for external validation of our results.
  
  
  RESULTS
  Gli-1 (p = 0.04) and Gli-2 (p = 0.02) overexpression was significantly linked to improved overall survival of HPV negative patients. Gli-2 (p = 0.04) overexpression correlated significantly with prolonged disease-free survival. Cox-multivariate analysis showed that overexpression of Gli-2 correlated independently (HR 0.40, 95% CI 0.16-0.95, p = 0.03) with increased overall survival.
  
  
  CONCLUSIONS
  Gli-1 and Gli-2 overexpression represents a substantial prognostic factor for overall and disease-free survival in patients with locally advanced HPV negative head and neck cancer undergoing surgery and postoperative radiotherapy.
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Enzenhofer
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Parzefall
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Haymerle
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Sven
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Kadletz
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Gregor
authors.initials: G
authors.lastname: Heiduschka
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Pammer
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Felicitas
authors.initials: F
authors.lastname: Oberndorfer
authors.affiliation: Department of Clinical Pathology, Medical University of Vienna, Vienna, Austria.
authors.forename: Fritz
authors.initials: F
authors.lastname: Wrba
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Rudolfstiftung, Vienna, Austria.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Loader
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Matthäus Christoph
authors.initials: MC
authors.lastname: Grasl
authors.affiliation: Department of Oral and Maxillofacial Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Christos
authors.initials: C
authors.lastname: Perisanidis
authors.affiliation: Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Vienna, Vienna, Austria.
authors.forename: Boban M
authors.initials: BM
authors.lastname: Erovic
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000532:radiotherapy / Q000601:surgery; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000532:radiotherapy / Q000601:surgery; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D027383:Papillomaviridae / Q000472:pathogenicity; D030361:Papillomavirus Infections / Q000378:metabolism; D011446:Prospective Studies; D018714:Radiotherapy, Adjuvant / Q000379:methods; D015398:Signal Transduction / Q000502:physiology; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D053823:Hedgehog Proteins