Mutationsanalyse des "epidermal growth factor receptors" beim nichtkleinzelligen Bronchialkarzinom

Zusammenfassung Das Bronchialkarzinom ist mittlerweile in den Vereinigten Staaten die häufigste Todesursache maligner Neoplasien bei Männern und Frauen. Trotz umfassender Veränderungen in der Diagnostik und Therapie hat sich die Prognose in den letzten Jahren kaum verändert. Nur wenige Patient...

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Bibliographic Details
Main Author: Theisen, Christina
Contributors: Ritter, Markus (Dr.) (Thesis advisor)
Format: Doctoral Thesis
Published: Philipps-Universität Marburg 2008
Online Access:PDF Full Text
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Table of Contents: Abstract Lung cancer remains the highest cause of cancer-related mortality in the United States and Western Europe. Despite comprehensive changes in diagnostic and therapies the prognosis of patients with nsclc has not changed a lot in the last few years. Only less patients have hope for recovery. Since nsclc usually presents with disseminated disease, treatment strategies have focused on systematic therapy. Mutations in EGFR tyrosine kinase domain define a new molecular type of lung carcinoma and are more frequent in a subset of patients. These somatic mutations are reportedly assosiated with sensitvity to TK-inhibitors like gefitinib or erlotinib. The development of specific blocking agents so as the EGFR-inhibitors represent new promising drugs in the therapy of lung cancer. The inhibition of EGFR by specific blocking agents induces apoptosis and reduces proliferation of tumor growth by competitive inhibition of the binding of adenosine triphosphate to the TK domain of the receptor, resulting in inhibition of the EGFR signaling pathway. Several studies found heterozygous mutations within the TK domain of mutations within the EGFR gene of patients with nsclc who had response to the therapy with gefitinib, an inhibitor of the TK domain. Retrospective epidemiologic analysis suggested that the mutations within the TK domain are more frequent in patients with asian origin, individuals with adenocarcinoma subtype, young womens and „never smokers“. Aim oft he present study was the establishment of a sensitive method to detect patients with non small cell lung cancer who carry a mutation within the exon 19 or 21. We examined 62 patients retrospectivley for EGFR-mutations in exon 19 and 21 using polymerase chain reaction, SSCP-analysis and DNA-sequencing. 11% mutations were found in the series oft he 62 examined patients with nsclc. The SSCP (PCR single-strand-conformation)-analysis was accurate and sensitive, allowing identification and confirmation of the mutations by direct sequencing. Our result is equal to the findings of the current academic situation. The performed methods in our study are easy to reproduce and practical in performance. The SSCP assay is a rapid and reliable method for the detection of EGFR kinase domain mutations in lung cancer.