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Updated: May 3, 2026
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
CD74-NRG1 fusions in lung adenocarcinoma
Lynnette Fernandez-Cuesta1, Dennis Plenker, Hirotaka Osada
11Department 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.
Insights
A novel CD74-NRG1 gene fusion was found in lung adenocarcinomas, particularly the invasive mucinous subtype. This discovery offers a potential new therapeutic target for this difficult-to-treat lung cancer.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) comprises various subtypes with distinct molecular drivers.
- Invasive mucinous adenocarcinoma is a subtype of LUAD with limited targeted treatment options.
- Identifying novel oncogenic alterations is crucial for developing new therapies.
Purpose of the Study:
- To discover novel somatic gene fusions in lung adenocarcinomas, especially in never-smokers.
- To investigate the functional consequences of the identified CD74-NRG1 fusion.
- To explore the therapeutic potential of targeting CD74-NRG1 fusions in invasive mucinous adenocarcinomas.
Main Methods:
- Transcriptome sequencing was performed on lung adenocarcinoma samples.
- Screening for gene fusions was conducted in tumors lacking known oncogenic alterations.
- Functional assays were used to assess the impact of CD74-NRG1 on cellular pathways and growth.
Main Results:
- A novel CD74-NRG1 gene fusion was identified in lung adenocarcinomas, predominantly in the invasive mucinous subtype.
- The CD74-NRG1 fusion activates the ERBB2-ERBB3 receptor pathway.
- Activation of this pathway leads to downstream signaling (PI3K-AKT) and promotes tumor cell growth.
Conclusions:
- CD74-NRG1 gene fusions are oncogenic drivers in invasive mucinous lung adenocarcinomas.
- These fusions represent a potential therapeutic target for a lung cancer subtype with unmet clinical needs.
- Targeting CD74-NRG1 may offer a new treatment strategy for patients with multifocal, unresectable disease.
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