Analysis of mutation-specific Epidermal Growth Factor Receptor (E746-A750del) and human papillomavirus in oral squamous cell carcinoma

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Dokumentart: PhDThesis
Date: 2015-06
Language: English
Faculty: 4 Medizinische Fakultät
Department: Zahnmedizin
Advisor: Grimm, Martin (PD Dr. Dr.)
Day of Oral Examination: 2015-05-12
DDC Classifikation: 610 - Medicine and health
Keywords: Epidermaler Wachstumsfaktor-Rezeptor
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Summary Oral squamous cell carcinoma (OSCC) takes the sixth place among the most common cancers worldwide. In spite of the vast amount of research and the advances in diagnosis and treatment modalities, the survival rates of patients with oral cancer have not significantly improved in the last decades. Prognostic and predictive biomarkers of treatment outcome have been identified as causative factors for other tumor entities but they are still lacking for OSCC. The primary purpose of this study is the analysis of two important biomarkers - Epidermal Growth Factor Receptor (EGFR) and human papillomavirus (HPV), which may have a promising impact on the diagnosis and therapy of OSCC. It has become apparent that an abnormal activation of EGFR gene is correlated with self-sufficiency in growth signals, evading apoptosis and other hallmarks of cancer. Moreover, EGFR (E746-A750del) mutations can increase the sensitivity to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib in patients with advanced non-small-cell lung cancer. Therefore, testing for mutations in EGFR is an important step in the treatment-decision-pathway. However, the prognostic impact of EGFR (E746-A750del) mutation and HPV on OSCC remains unclear. This study was designed to analyze the clinical impact of EGFR (E746-A750del) mutation and human papillomavirus (HPV) in OSCC. 211 patients with OSCC treated by primary radical tumor resection were retrospectively enrolled in this study. Using INNO-LiPA Extra, high-risk-HPV types were analyzed in all 211 OSCC samples. The EGFR (E746-A750del) expression was analyzed in 161 OSCC samples by immunohistochemistry. The expression results were associated with clinicopathological characteristics and survival outcome. The disease-free survival times were estimated using the Kaplan-Meier method. Multivariate analysis using the Cox Proportional Hazards Model was not performed for these parameters. Our findings showed low prevalence of EGFR (E746-A750del) expression and HPV in all cancer specimens. Positive EGFR (E746-A750del) expression was detected in 25% of the patients (n = 40/161), while 1.42% of them were HPV16 positive (HPV16+: n = 3/211). EGFR (E746-A750del) mutation was not significantly associated with survival of the patients. Lymph node metastasis was shown to be the only significant unfavorable factor in multivariate analysis. Social habits like alcohol consumption or smoking had no significant effect on the tumor specific survival. Positive HPV status had no impact on tumor specific survival in OSCC. On the basis of the results of this research it can be concluded that in OSCC EGFR (E746-A750del) expression is not associated with clinicopathological characteristics, prognostic factors, or social habits; HPV does not seem to be correlated with the survival of patients. Our results may contribute to a better understanding of the prognostic impact of EGFR mutations and HPV in OSCC leading to guidance on better diagnosis and therapeutic decisions in the future. Further studies are needed to investigate the prognostic impact of EGFR mutations in OSCC particularly in relation to small molecules.

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