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Identification of Metastasis-Associated Receptor Tyrosine Kinases in Non–Small Cell Lung Cancer

¹ Department of Medicine, Hematology/Oncology; ² Department of Medicine, Gastroenterology, University of Münster, Münster; and ³ Department of Visceral and Vascular Surgery, University of Cologne, Cologne, Germany

Requests for reprints: Carsten Müller-Tidow, Department of Medicine A, Hematology/Oncology, University of Münster, Domagkstr. 3, 48149 Münster, Germany. Phone: 49-251-835-6229; Fax: 49-251-835-2673; E-mail: muellerc{at}uni-muenster.de.

Development of distant metastasis after tumor resection is the leading cause of death in early-stage non–small cell lung cancer (NSCLC). Receptor tyrosine kinases (RTK) are involved in tumorigenesis but only few RTKs have been systematically studied in NSCLC. Here, we provide quantitative real-time reverse transcription-PCR expression data of all RTKs (n = 56) in primary tumors of 70 patients with early-stage (I-IIIA) NSCLC. Overall, 33 RTKs were expressed in at least 25% of the patients. Several RTKs were significantly expressed higher in tumors that ultimately metastasized. The hazard risk for metastasis development in stage I/II disease was increased at least 3-fold for tumors with high expression levels of insulin receptor, neurotrophic tyrosine receptor kinase 1, epidermal growth factor receptor, ERBB2, ERBB3, platelet-derived growth factor receptor ß, fibroblast growth factor receptor 1, or leukocyte tyrosine kinase. Relative risks were reduced 3-fold by expression of EPHB6 or DKFZ1. Three members of the epidermal growth factor receptor family were associated with a high risk of metastasis, emphasizing the validity of our data. High ERBB3 expression was significantly associated with decreased survival. Taken together, our genome-wide RTK expression map uncovered the previously unknown value of several RTKs as potential markers for prognosis and metastasis prediction in early-stage NSCLC. The identified RTKs represent promising novel candidates for further functional analyses.

Key Words: lung cancer • NSCLC • metastasis • prognosis • receptor tyrosine kinase

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