title: Molecular profile of head and neck squamous cell carcinomas bearing p16 high phenotype.
abstract: BACKGROUND
  We sought to determine biomarker expression differences in head and neck squamous cell cancers (HNSCCs) based on p16/human papillomavirus (HPV) classification. In addition, our aim was to explore how expression of biomarkers is modulated after E6/E7 repression in HPV16⁺ oropharyngeal cancer cells.
  
  
  METHODS
  HPV16⁺ and HPV⁻ HNSCC cells were infected with retroviruses expressing short hairpin RNA targeting HPV16 E6/E7. Components of the epidermal growth factor receptor (EGFR) pathway before and after E6/E7 gene silencing were analyzed by immunoblotting and qRT-PCR. Protein expression of 13 biomarkers was analyzed using AQUA on a tissue microarray (TMA). The HPV16 status was determined using HPV16 in situ hybridization (ISH).
  
  
  RESULTS
  In HPV16⁺ cells, E6/E7 silencing was associated with PTEN upregulation and reduction of phosphorylated EGFR. Tumors were classified into four categories based on the HPV and p16 status. HPV⁺/p16⁺ tumors expressed significantly higher levels of E-cadherin (P = 0.003), PTEN (P = 0.004), lower levels of PI3Kp110 and β-catenin (P = 0.07). There was a significant difference in overall survival (OS, P = 0.016) among the four subsets. The median OS was 24.83 months for p16⁻/HPV⁻ patients, 11.63 for p16⁻/HPV⁺ patients and was not reached for p16⁺/HPV⁻ and p16⁺/HPV⁺ groups.
  
  
  CONCLUSIONS
  Aberrant EGFR signaling contributes to malignant conversion of HPV16⁺ HNSCC cells. These results validate β-catenin as a distinct biomarker in HPV⁺/p16⁺ HNSCC. Wnt signaling inhibitors merit exploration in HPV⁺/p16⁺ HNSCC.
authors: Department of Surgery (Otolaryngology), Yale University School of Medicine, New Haven, CT, USA.
authors: T
authors: T
authors: Rampias
authors: E
authors: E
authors: Pectasides
authors: M
authors: M
authors: Prasad
authors: C
authors: C
authors: Sasaki
authors: P
authors: P
authors: Gouveris
authors: A
authors: A
authors: Dimou
authors: P
authors: P
authors: Kountourakis
authors: C
authors: C
authors: Perisanidis
authors: B
authors: B
authors: Burtness
authors: T
authors: T
authors: Zaramboukas
authors: D
authors: D
authors: Rimm
authors: G
authors: G
authors: Fountzilas
authors: A
authors: A
authors: Psyrri
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000378:metabolism; D009959:Oropharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis; D050725:Papillomavirus E7 Proteins / Q000235:genetics / Q000378:metabolism; D030361:Papillomavirus Infections / Q000150:complications / Q000235:genetics / Q000821:virology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000077195:Squamous Cell Carcinoma of Head and Neck; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; C068651:E6 protein, Human papillomavirus type 16; D009363:Neoplasm Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; C059731:oncogene protein E7, Human papillomavirus type 16; C512478:EGFR protein, human; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: EGFR; HNSCC; Wnt; p16+