CD74-NRG1 fusions in lung adenocarcinoma.
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.


CONCLUSIONS
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.
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.
Lynnette
L
Fernandez-Cuesta
Dennis
D
Plenker
Hirotaka
H
Osada
Ruping
R
Sun
Roopika
R
Menon
Frauke
F
Leenders
Sandra
S
Ortiz-Cuaran
Martin
M
Peifer
Marc
M
Bos
Juliane
J
Daßler
Florian
F
Malchers
Jakob
J
Schöttle
Wenzel
W
Vogel
Ilona
I
Dahmen
Mirjam
M
Koker
Roland T
RT
Ullrich
Gavin M
GM
Wright
Prudence A
PA
Russell
Zoe
Z
Wainer
Benjamin
B
Solomon
Elisabeth
E
Brambilla
Hélène
H
Nagy-Mignotte
Denis
D
Moro-Sibilot
Christian G
CG
Brambilla
Sylvie
S
Lantuejoul
Janine
J
Altmüller
Christian
C
Becker
Peter
P
Nürnberg
Johannes M
JM
Heuckmann
Erich
E
Stoelben
Iver
I
Petersen
Joachim H
JH
Clement
Jörg
J
Sänger
Lucia A
LA
Muscarella
Annamaria
A
la Torre
Vito M
VM
Fazio
Idoya
I
Lahortiga
Timothy
T
Perera
Souichi
S
Ogata
Marc
M
Parade
Dirk
D
Brehmer
Martin
M
Vingron
Lukas C
LC
Heukamp
Reinhard
R
Buettner
Thomas
T
Zander
Jürgen
J
Wolf
Sven
S
Perner
Sascha
S
Ansén
Stefan A
SA
Haas
Yasushi
Y
Yatabe
Roman K
RK
Thomas
D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D000077192:Adenocarcinoma of Lung; D002288:Adenocarcinoma, Mucinous / Q000235:genetics* / Q000473:pathology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics*; D001483:Base Sequence; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D020890:Neuregulin-1 / Q000235:genetics*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
D000944:Antigens, Differentiation, B-Lymphocyte; D000949:Histocompatibility Antigens Class II; C094131:NRG1 protein, human; D020890:Neuregulin-1; D015514:Oncogene Proteins, Fusion; C045084:invariant chain