CD74-NRG1 fusions in lung adenocarcinoma

Lynnette Fernandez-Cuesta, Dennis Plenker, Hirotaka Osada, Ruping Sun, Roopika Menon, Frauke Leenders, Sandra Ortiz-Cuaran, Martin Peifer, Marc Bos, Juliane Daßler, Florian Malchers, Jakob Schöttle, Wenzel Vogel, Ilona Dahmen, Mirjam Koker, Roland T. Ullrich, Gavin M. Wright, Prudence A. Russell, Zoe Wainer, Benjamin SolomonElisabeth Brambilla, Héléne Nagy-Mignotte, Denis Moro-Sibilot, Christian G. Brambilla, Sylvie Lantuejoul, Janine Altmüller, Christian Becker, Peter Nürnberg, Johannes M. Heuckmann, Erich Stoelben, Iver Petersen, Joachim H. Clement, Jörg Sänger, Lucia A. Muscarella, Annamaria la Torre, Vito M. Fazio, Idoya Lahortiga, Timothy Perera, Souichi Ogata, Marc Parade, Dirk Brehmer, Martin Vingron, Lukas C. Heukamp, Reinhard Buettner, Thomas Zander, Jürgen Wolf, Sven Perner, Sascha Ansén, Stefan A. Haas, Yasushi Yatabe, Roman K. Thomas

Research output: Contribution to journalArticlepeer-review

130 Scopus citations

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-β3, 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.

Original languageEnglish (US)
Pages (from-to)415-422
Number of pages8
JournalCancer discovery
Volume4
Issue number4
DOIs
StatePublished - Apr 2014
Externally publishedYes

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