CD74-NRG1 fusions in lung adenocarcinoma.

Cancer Discov 2014 Apr 27;4(4):415-22. Epub 2014 Jan 27.

1Department of Translational Genomics; 2Department I of Internal Medicine; 3Laboratory of Translational Cancer Genomics; 4Network Genomic Medicine, University Hospital Cologne, Center of Integrated Oncology Cologne-Bonn; 5Center for Molecular Medicine Cologne (CMMC); 6Cologne Center for Genomics (CCG); 7Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD); 8Department of Pathology, University Hospital Medical Center, University of Cologne; 9Blackfield AG; 10Max Planck Institute for Neurological Research; 11Thoracic Surgery, Lungenklinik Merheim, Kliniken der Stadt Köln gGmbH; 12Institute of Human Genetics, Cologne; 13Computational Molecular Biology Department, Max Planck Institute for Molecular Genetics, Berlin; 14Department of Prostate Cancer Research, Institute of Pathology; 15Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Bonn; 16Institute of Pathology; 17Department of Internal Medicine II, Jena University Hospital, Friedrich-Schiller-University, Jena; 18Institute for Pathology Bad Berka, Bad Berka, Germany;19Division of Molecular Oncology, Aichi Cancer Center Research Institute; 20Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, Nagoya, Japan; Departments of 21Surgery and22Pathology, St. Vincent's Hospital; 23Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia;24Department of Pathology, 25CHU Grenoble Institut National de la Santé et de la Recherche Medicale (INSERM) U823, Institute Albert Bonniot, Grenoble-Alpes University, Grenoble, France; 26Laboratory of Oncology IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo; 27Laboratory for Molecular Medicine and Biotechnology, University Campus Bio-Medico, Rome, Italy; 28Center for the Biology of Disease, VIB, Leuven; and 29Oncology Discovery, Janssen Research and Development, A Division of Janssen Pharmaceutica NV, Beerse, Belgium.

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.

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http://dx.doi.org/10.1158/2159-8290.CD-13-0633DOI Listing
April 2014
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