title: Receptor tyrosine kinase profiles and human papillomavirus status in oropharyngeal squamous cell carcinoma.
abstract: BACKGROUND
  Human papillomavirus (HPV)-positive and HPV-negative oropharyngeal squamous cell carcinomas (OSCCs) are two distinct entities. We defined the molecular profiles of druggable receptor tyrosine kinases (RTKs) in both groups.
  
  
  METHODS
  E5 expression and RTK alterations were studied in 17 HPV-positive and 59 HPV-negative formalin-fixed OSCCs. RTK activation was explored in further 12 frozen OSCCs.
  
  
  RESULTS
  The HPV-positive OSCCs showed E5 expression and 33.3% expressed low level of HER2. The HPV-negative OSCCs showed HER2 expression (31.2%), increased HER2 gene copy number (46.51%, P = 0.045) and HER2 activation through HER2/EGFR heterodimerisation; HER3 (51.06%, P = 0.008) and neuregulin (65.63%; P = 0.03) expression, HER3 activation and HER3/EGFR heterodimerisation; and increased IGF-1R copy number (40.50%, P = 0.021), high IGF-1R cDNA values (P = 0.002), IGF-1R activation and expression of IGF1/2 and amphiregulin. PI3KCA mutations/expression/increased gene copy number and PTEN mutations were found in both groups, whereas PTEN gene loss was only observed in the HPV-positive cases.
  
  
  CONCLUSIONS
  Human papillomavirus-positive and HPV-negative OSCC showed different RTK profiles. In HPV-positive cases, it would be interesting to study the expression of E5, which may modulate EGFR turnover and activate VEGF and PDGFRβ. In HPV-negative cases, HER3 may be a promising druggable biomarker that deserves further investigation. PI3KCA and PTEN alterations encourage the promising clinical evaluation of PI3K/mTOR inhibitor activity in OSCC, particularly in HPV-positive/PI3KCA-mutated OSCCs because they may be driven by PI3KCA mutation alone.
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cortelazzi
authors.affiliation: Unit of Medical Statistics Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Verderio
authors.affiliation: Unit of Medical Statistics Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Chiara Maura
authors.initials: CM
authors.lastname: Ciniselli
authors.affiliation: Unit of Medical Statistics Biometry and Bioinformatics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Pizzamiglio
authors.affiliation: Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bossi
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Annunziata
authors.initials: A
authors.lastname: Gloghini
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Ambra V
authors.initials: AV
authors.lastname: Gualeni
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Chiara C
authors.initials: CC
authors.lastname: Volpi
authors.affiliation: Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Locati
authors.affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Pierotti
authors.affiliation: Head and Neck Cancer Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
mesh_terms: D066258:Amphiregulin / Q000235:genetics / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000473:pathology / Q000821:virology*; D006801:Humans; D009062:Mouth Neoplasms / Q000473:pathology; D009154:Mutation; D009959:Oropharyngeal Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000821:virology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D020794:Receptor Protein-Tyrosine Kinases / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D066258:Amphiregulin; D014408:Biomarkers, Tumor; D051059:PTEN Phosphohydrolase; D010446:Peptide Fragments; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D016211:Transforming Growth Factor alpha; C561872:HER2 peptide (369-377); C494929:PTEN protein, human
keywords: HER3; HR-HPV; IGF-1R; PIK3CA; oropharyngeal squamous cell carcinomas