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

Purpose: 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.

Patients and 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.

Conclusion: 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.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

Representative images of automated quantitative protein expression analysis (AQUA) of head and neck squamous cell cancer and the control tissues; (A) glioma-associated oncogene family zinc finger 1, and (B) beta-catenin. DAPI, 4,6-diamidino-2-phenylindole-2-HCI.

Fig 2.

Cumulative incidence functions (A-C) and Kaplan-Meier survival curves (D) according to risk groups defined by quartiles (Q) of glioma-associated oncogene family zinc finger 1 (GL1) expression (low, Q1 to Q3 v high, Q4) and the median of epidermal growth factor receptor (EGFR) expression (low, ≤ median v high, > median), and a combination of the groups by both GL1 and EGFR expression levels; (A) time to regional-distant metastasis, (B) time to distant metastasis, (C) time to disease progression, and (D) overall survival.

Fig A1.

Schematic diagram of hedgehog (Hh) -GLI signaling pathway based on published reviews.,, HHIP, hedgehog interacting protein; PTCH1, patched 1; SMO, smoothened; DISP1, dispatched homolog 1; FBXW1/β-TRCP, beta-transducin repeat containing; GLI1, glioma-associated oncogene family zinc finger 1; KIF, Costal-2 homologs; STK36, serine/threonine kinase 36; SUFU, suppressor of fused homolog; FOXM1, forkhead box M1; CCND2, cyclin D2.