title: Glioma-associated oncogene family zinc finger 1 expression and metastasis in patients with head and neck squamous cell carcinoma treated with radiation therapy (RTOG 9003).
abstract: OBJECTIVE
  Glioma-associated oncogene family zinc finger 1 (GLI1) expression was assessed to determine a potential role of hedgehog (Hh) signaling in head and neck squamous cell carcinoma (HNSCC). Additional proteins known to be modulated by Hh signaling, including beta-catenin (CTNNB1) and epidermal growth factor receptor (EGFR), were also assessed to determine the correlation among these distinct signaling pathways.
  
  
  METHODS
  Nuclear GLI1 and CTNNB1 expression levels were determined in tumors from patients enrolled on Radiation Therapy Oncology Group (RTOG) 9003, a radiation fractionation trial. The results were also correlated with previously determined EGFR expression. The expression levels were evaluated in relation to three end points: time to metastasis (TTM), time to disease progression (TDP), and overall survival (OS).
  
  
  RESULTS
  Among 1,068 eligible patients, data on GLI1, CTNNB1, and EGFR were available in 339, 164, and 300 patients, respectively. Although CTNNB1 expression did not differentiate prognosis, GLI1 was associated with poorer outcomes, adjusted for age, TNM stages, and Karnofsky performance score, and the significant influence persisted in a multivariable analysis (quartile 4 [Q4] v Q1 to Q3: TTM hazard ratio [HR], 2.7; 95% CI, 1.5 to 4.9; TDP HR, 1.6; 95% CI, 1.1 to 2.5; OS HR, 1.9; 95% CI, 1.4 to 2.7). The significance of GLI1 persisted in a multivariable analysis that included EGFR expression levels.
  
  
  CONCLUSIONS
  These data suggest that Hh signaling may play an important role in metastasis and that GLI1 could serve as a marker in HNSCC, but the regulatory mechanisms and oncogenic significance need further investigation. Risk classification based on this analysis needs a validation in independent cohorts.
authors.affiliation: Department of Oncology, Johns Hopkins University School of Medicine, 1650 Orleans St, CRB-1 Room 344, Baltimore, MD 21231-1000, USA. cchung11@jhmi.edu
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: James J
authors.initials: JJ
authors.lastname: Dignam
authors.forename: M Elizabeth
authors.initials: ME
authors.lastname: Hammond
authors.forename: Alexander C
authors.initials: AC
authors.lastname: Klimowicz
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Petrillo
authors.forename: Anthony
authors.initials: A
authors.lastname: Magliocco
authors.forename: Richard
authors.initials: R
authors.lastname: Jordan
authors.forename: Andy
authors.initials: A
authors.lastname: Trotti
authors.forename: Sharon
authors.initials: S
authors.lastname: Spencer
authors.forename: Jay S
authors.initials: JS
authors.lastname: Cooper
authors.forename: Quynh-Thu
authors.initials: QT
authors.lastname: Le
authors.forename: K Kian
authors.initials: KK
authors.lastname: Ang
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis*; D002170:Canada; D002294:Carcinoma, Squamous Cell / Q000737:chemistry / Q000401:mortality / Q000532:radiotherapy* / Q000556:secondary; D018450:Disease Progression; D019583:Dose Fractionation, Radiation; D066246:ErbB Receptors / Q000032:analysis; D005260:Female; D006258:Head and Neck Neoplasms / Q000737:chemistry / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D018570:Risk Assessment; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D046888:Tissue Array Analysis; D014157:Transcription Factors / Q000032:analysis*; D016896:Treatment Outcome; D014481:United States; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C495270:CTNNB1 protein, human; C400551:GLI1 protein, human; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D051176:beta Catenin; C512478:EGFR protein, human; D066246:ErbB Receptors