CD74-NRG1 fusions in lung adenocarcinoma.

Abstract

UNLABELLED:

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.

• Authors: 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 Solomon, Elisabeth Brambilla, Hélène 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
• Journal: Cancer discovery (Cancer Discov) Vol. 4 Issue 4 Pg. 415-22 (Apr 2014) ISSN: 2159-8290 [Electronic] United States
• PMID: 24469108 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, Differentiation, B-Lymphocyte
• Histocompatibility Antigens Class II
• NRG1 protein, human
• Neuregulin-1
• Oncogene Proteins, Fusion
• invariant chain

Topics

• Adenocarcinoma (genetics, pathology)
• Adenocarcinoma of Lung
• Adenocarcinoma, Mucinous (genetics, pathology)
• Adult
• Aged
• Aged, 80 and over
• Animals
• Antigens, Differentiation, B-Lymphocyte (genetics)
• Base Sequence
• Cell Line, Tumor
• Female
• Gene Expression Profiling
• Histocompatibility Antigens Class II (genetics)
• Humans
• Lung Neoplasms (genetics, pathology)
• Male
• Mice
• Middle Aged
• Molecular Sequence Data
• NIH 3T3 Cells
• Neuregulin-1 (genetics)
• Oncogene Proteins, Fusion (genetics, metabolism)
• Sequence Analysis, DNA
• Signal Transduction (genetics)