Simultaneous over activation of EGFR, telomerase (h TERT), and cyclin D1 correlates with advanced disease in larynx squamous cell carcinoma: a tissue microarray analysis

Abstract

Overexpression of Epidermal Growth Factor Receptor (EGFR) and also of cell cycle control proteins, such as cyclin D1 is a frequent event in squamous cell carcinoma of the larynx (LSSC). Our aim was to correlate their protein levels with telomerase catalytic subunit (h-TERT) expression. Using tissue microarray technology, fifty-five paraffin embedded histologically confirmed primary LSSCs and also ten dysplastic lesions were cored at a diameter of 1.5 mm. Immunohistochemistry (IHC) was performed by the use of anti-EGFR, anti-cyclin D1, and anti-h TERT monoclonal antibodies. Chromogenic in situ hybridization (CISH) analysis was also applied using EGFR gene and chromosome 7 probes, respectively. EGFR, cyclin D1 and h-TERT protein overexpression was observed in 48/55 (87.2%), 19/55 (34.5%) and 21/55 (38.1%) carcinoma cases, respectively. EGFR protein expression was statistically associated with grade (P=0.01), and also with stage (P=0.001) of the examined tumors. Borderline statistical significance was assessed correlating overall cyclin D1 expression to h TERT expression (P=0.06). Simultaneous up regulation of the three proteins was established in 7/55 (12.7%) cases, correlated to the stage of the tumors (P=0.05). EGFR gene amplification was observed in 7/65 (10.7%) carcinomas and dysplasias, whereas chromosome 7 aneuploidy was detected in 4/65 (6.1%) of those cases.Simultaneous up regulation of EGFR, cyclin D1 and h TERT proteins correlates with advanced stage in LSCC. EGFR gene amplification and not only protein over expression maybe is the eligible criterion for targeted therapeutic strategies in those patients.

Increased telomerase activity and hTERT expression in human salivary gland carcinomas

“…Recently, Heeg et al reported that EGFR leads to the phosphorylation of hTERT and regulates telomerase activity through the PI3K/ AKT signaling pathway (31). Combined EGFR, cyclin D1 and hTERT protein expression was correlated with an aggressive phenotype in squamous cell carcinoma of the larynx (32). In the present study, a significant correlation was found between the expression of EGFR mRNA and telomerase activity.…”

EGFR expression and copy number changes in low T‐stage oral squamous cell carcinomas

“…Such a combined pattern was described recently as an independent marker of worse overall survival . Previous studies using immunohistochemistry for assessment of EGFR protein expression report EGFR overexpression in most (≥80%) oral and other head and neck SCC . This limits the value of EGFR protein expression as a prognostic or predictive biomarker and makes comparison of protein expression with EGFR copy number changes more difficult.…”

“…EGFR mutation is rare in head and neck SCC (0–7.3%) and has been detected only in laryngeal carcinoma . EGFR protein overexpression has been detected using immunohistochemistry in most (≥80%) oral and other head and neck SCC, but its prognostic and predictive value is controversial . Increased EGFR gene copy number was detected in up to 58% of oral SCC, but correlation of increased gene copy number with survival or treatment response generated conflicting results in patients with head and neck SCC …”

Telomeres and telomerase in head and neck squamous cell carcinoma: from pathogenesis to clinical implications

“…Telomerase can be associated, alone or together with other markers, with a more aggressive phenotype and behavior in HNSCC. Several studies have, indeed, reported that TERT mRNA levels and telomerase activity are higher in poorly differentiated SCC [ 63 , 126 , 143 , 146 , 166 – 169 ], increase with tumor stage [ 63 , 131 , 142 , 166 ], and are associated with lymph node involvement [ 63 , 126 , 131 , 137 , 139 , 170 ] or extracapsular extension of lymph node metastases [ 125 ]. Numerous studies have analyzed telomerase’s ability to predict outcome (Table 1 ) [ 46 , 63 , 125 , 127 , 130 , 136 , 139 , 140 , 144 , 171 – 177 ], and most have reported a correlation between increased telomerase expression and activity and a reduced response to treatment and a higher rate of regional and distant metastases ultimately resulting in poor clinical outcome [ 63 , 125 , 127 , 136 , 144 , 171 , 173 – 176 ].…”