Schildhaus, Hans-Ulrich, Schultheis, Anne M., Rueschoff, Josef, Binot, Elke, Merkelbach-Bruse, Sabine, Fassunke, Jana, Schulte, Wolfgang, Ko, Yon-Dschun, Schlesinger, Andreas, Bos, Marc, Gardizi, Masyar, Engel-Riedel, Walburga, Brockmann, Michael, Serke, Monika, Gerigk, Ulrich, Hekmat, Khosro, Frank, Konrad F., Reiser, Marcel, Schulz, Holger, Krueger, Stefan, Stoelben, Erich, Zander, Thomas, Wolf, Juergen and Buettner, Reinhard (2015). MET Amplification Status in Therapy-Naive Adeno- and Squamous Cell Carcinomas of the Lung. Clin. Cancer Res., 21 (4). S. 907 - 916. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1557-3265

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Abstract

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-naive 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-naive 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 additionally to MET amplification and, thus, may not benefit from MET inhibition. Furthermore, our study provides comprehensive epidemiologic data for upcoming trials with various MET inhibitors. (C) 2014 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schildhaus, Hans-UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schultheis, Anne M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rueschoff, JosefUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Binot, ElkeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Merkelbach-Bruse, SabineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fassunke, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulte, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ko, Yon-DschunUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schlesinger, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bos, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gardizi, MasyarUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Engel-Riedel, WalburgaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brockmann, MichaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Serke, MonikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gerigk, UlrichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hekmat, KhosroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Frank, Konrad F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reiser, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schulz, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoelben, ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JuergenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-407629
DOI: 10.1158/1078-0432.CCR-14-0450
Journal or Publication Title: Clin. Cancer Res.
Volume: 21
Number: 4
Page Range: S. 907 - 916
Date: 2015
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 1557-3265
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE COPY NUMBER; IN-SITU HYBRIDIZATION; RECEPTOR TYROSINE KINASE; GROWTH-FACTOR RECEPTOR; CANCER PATIENTS; FGFR1 AMPLIFICATION; PROTEIN EXPRESSION; GEFITINIB; TARGET; RESISTANCEMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/40762

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