Fernandez-Cuesta, Lynnette ORCID: 0000-0002-0724-6703, Plenker, Dennis, Osada, Hirotaka, Sun, Ruping, Menon, Roopika, Leenders, Frauke, Ortiz-Cuaran, Sandra, Peifer, Martin ORCID: 0000-0002-5243-5503, Bos, Marc, Dassler, Juliane, Malchers, Florian, Schottle, Jakob, Vogel, Wenzel, Dahmen, Ilona, Koker, Mirjam, Ullrich, Roland T., Wright, Gavin M., Russell, Prudence A., Wainer, Zoe, Solomon, Benjamin, Brambilla, Elisabeth, Nagy-Mignotte, Helene, Moro-Sibilot, Denis, Brambilla, Christian G., Lantuejoul, Sylvie, Altmuller, Janine, Becker, Christian, Nurnberg, Peter, Heuckmann, Johannes M., Stoelben, Erich, Petersen, Iver, Clement, Joachim H. ORCID: 0000-0002-6601-2456, Saenger, Joerg, Muscarella, Lucia A., la Torre, Annamaria ORCID: 0000-0003-4199-1077, Fazio, Vito M., Lahortiga, Idoya, Perera, Timothy, Ogata, Souichi, Parade, Marc, Brehmer, Dirk, Vingron, Martin, Heukamp, Lukas C., Buettner, Reinhard, Zander, Thomas, Wolf, Jurgen, Perner, Sven, Ansen, Sascha, Haas, Stefan A., Yatabe, Yasushi ORCID: 0000-0003-1788-559X and Thomas, Roman K. (2014). CD74-NRG1 Fusions in Lung Adenocarcinoma. Cancer Discov., 4 (4). S. 415 - 423. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 2159-8290

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Abstract

We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III- ss 3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion ( P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. SIGNIFICANCE: CD74-NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. Cancer Discov; 4(4); 415- 22. (c) 2014 AACR.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Fernandez-Cuesta, LynnetteUNSPECIFIEDorcid.org/0000-0002-0724-6703UNSPECIFIED
Plenker, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Osada, HirotakaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sun, RupingUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Menon, RoopikaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Leenders, FraukeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ortiz-Cuaran, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Peifer, MartinUNSPECIFIEDorcid.org/0000-0002-5243-5503UNSPECIFIED
Bos, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dassler, JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Malchers, FlorianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schottle, JakobUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vogel, WenzelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dahmen, IlonaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koker, MirjamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ullrich, Roland T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wright, Gavin M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Russell, Prudence A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wainer, ZoeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Solomon, BenjaminUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambilla, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nagy-Mignotte, HeleneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Moro-Sibilot, DenisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brambilla, Christian G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lantuejoul, SylvieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmuller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nurnberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heuckmann, Johannes M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stoelben, ErichUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petersen, IverUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Clement, Joachim H.UNSPECIFIEDorcid.org/0000-0002-6601-2456UNSPECIFIED
Saenger, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Muscarella, Lucia A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
la Torre, AnnamariaUNSPECIFIEDorcid.org/0000-0003-4199-1077UNSPECIFIED
Fazio, Vito M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lahortiga, IdoyaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perera, TimothyUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ogata, SouichiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parade, MarcUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brehmer, DirkUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vingron, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heukamp, Lukas C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Buettner, ReinhardUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zander, ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wolf, JurgenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perner, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ansen, SaschaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Haas, Stefan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Yatabe, YasushiUNSPECIFIEDorcid.org/0000-0003-1788-559XUNSPECIFIED
Thomas, Roman K.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-441413
DOI: 10.1158/2159-8290.CD-13-0633
Journal or Publication Title: Cancer Discov.
Volume: 4
Number: 4
Page Range: S. 415 - 423
Date: 2014
Publisher: AMER ASSOC CANCER RESEARCH
Place of Publication: PHILADELPHIA
ISSN: 2159-8290
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CANCER; GENE; RET; ALK; IDENTIFICATION; ROS1Multiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44141

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