Ping Ji ^{1, 5}, Sven Diederichs ^{1, 5}, Wenbing Wang ¹, Sebastian Böing ¹, Ralf Metzger ², Paul M Schneider ², Nicola Tidow ³, Burkhard Brandt ³, Horst Buerger ⁴, Etmar Bulk ¹, Michael Thomas ¹, Wolfgang E Berdel1 ¹, Hubert Serve ¹ and Carsten Müller-Tidow ¹

¹ Department of Medicine, Hematology/Oncology, University of Münster, Germany
² Department of Visceral and Vascular Surgery, University of Cologne, Germany
³ Institute for Laboratory Medicine and Clinical Chemistry, University of Münster, Germany
⁴ Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany

Correspondence to: H Serve and C Müller-Tidow, Department of Medicine, Hematology/Oncology, University of Münster Domagkstr. 3, 48129 Münster, Germany.
E-mail:   muellerc@uni-muenster.de

⁵ Contributed equally
This work is supported by a grant from the Wilhelm Sander-Stiftung (2001.086.1)

Early-stage non-small cell lung cancer (NSCLC) can be cured by surgical resection, but a substantial fraction of patients ultimately dies due to distant metastasis. In this study, we used subtractive hybridization to identify gene expression differences in stage I NSCLC tumors that either did or did not metastasize in the course of
disease. Individual clones (n=225) were sequenced and quantitative RT-PCR verified overexpression in metastasizing samples. Several of the identified genes (eIF4A1, thymosin b4 and a novel transcript named MALAT-1) were demonstrated to be significantly associated with metastasis in NSCLC patients (n=70). The genes' association with metastasis was stage- and histology specific. The Kaplan-Meier analyses identified MALAT-1 and thymosin b4 as prognostic parameters for patient survival in stage I NSCLC. The novel MALAT-1 transcript is a noncoding RNA of more than 8000 nt expressed from chromosome 11q13. It is highly expressed in lung, pancreas and other healthy organs as well as in NSCLC. MALAT-1 expressed sequences are conserved across several species indicating its potentially important function. Taken together, these data contribute to the identification of early-stage NSCLC patients that are at high risk to develop metastasis. The identification of MALAT-1 emphasizes the potential role of noncoding RNAs in human cancer.

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