MET Amplification Status in Therapy-Naïve Adeno- and Squamous Cell Carcinomas of the Lung

作者：Hans‐Ulrich Schildhaus, Anne Maria Schultheis, Josef Rüschoff, Elke Binot, Sabine Merkelbach‐Bruse, Jana Fassunke, Wolfgang Schulte, Yon‐Dschun Ko, Andreas Schlesinger, Marc Christiaan Allardt Bos, Masyar Gardizi, Walburga Engel-Riedel, Michael Brockmann, Monika Heidi Serke, Ulrich Gerigk, Khosro Hekmat, Konrad F. Frank, Marcel Reiser, H. Schulz, Stefan Krüger, Erich Stoelben, Thomas Zander, Jürgen Wolf, Reinhard Buettner · 发表于：Clinical Cancer Research · 年份：2014 · DOI：10.1158/1078-0432.ccr-14-0450 · 被引用次数：192 · 研究领域：Liver physiology and pathology、Lung Cancer Treatments and Mutations、Hepatocellular Carcinoma Treatment and Prognosis

PURPOSE: MET is a potential therapeutic target in lung cancer and both MET tyrosine kinase inhibitors and monoclonal antibodies have entered clinical trials. MET signaling can be activated by various mechanisms, including gene amplification. In this study, we aimed to investigate MET amplification status in adeno- and squamous cell carcinomas of the lung. We propose clearly defined amplification scores and provide epidemiologic data on MET amplification in lung cancer. EXPERIMENTAL DESIGN: We evaluated the prevalence of increased MET gene copy numbers in 693 treatment-naïve cancers by FISH, defined clear cutoff criteria, and correlated FISH results to MET IHC. RESULTS: Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification (MET/centromer7 ratio ≥2.0 or average gene copy number per nucleus ≥6.0 or ≥10% of tumor cells containing ≥15 MET copies). The remaining cases can be subdivided into intermediate- (6%) and low-level gains (24%). Importantly, MET amplifications occur at equal frequencies in squamous and adenocarcinomas without or with EGFR or KRAS mutations. CONCLUSION: MET amplification is not a mutually exclusive genetic event in therapy-naïve non-small cell lung cancer. Our data suggest that it might be useful to determine MET amplification (i) before EGFR inhibitor treatment to identify possible primary resistance to anti-EGFR treatment, and (ii) to select cases that harbor KRAS mutations addition...