Abstract
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. 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). 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. 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.
Highlights
Clinical outcomes for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) have improved significantly with multimodality treatment approaches, that is not the case for patients with recurrence and/or distant metastasis
CTNNB1 expression did not differentiate prognosis, Glioma-associated oncogene family zinc finger 1 (GLI1) was associated with poorer outcomes, adjusted for age, TNM stages, and Karnofsky performance score, and the significant influence persisted in a multivariable analysis
The significance of GLI1 persisted in a multivariable analysis that included epidermal growth factor receptor (EGFR) expression levels
Summary
Clinical outcomes for patients with locally advanced head and neck squamous cell carcinoma (HNSCC) have improved significantly with multimodality treatment approaches, that is not the case for patients with recurrence and/or distant metastasis. Constitutive activation of the Hh pathway has been shown to play a critical role in tumorigenesis in malignant medulloblastoma, basal cell carcinoma of the skin, and breast, urogenital, GI, pancreatic, and lung cancers.[5,6,7,8,9,10,11,12,13,14] significant expression of proteins involved in Hh signaling has been reported,[15] the oncogenic role of protein expression has not been examined in HNSCC
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