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 Solomon & 31 others Elisabeth 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 journalArticle

105 Citations (Scopus)

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
Pages (from-to)415-422
Number of pages8
JournalCancer Discovery
Volume4
Issue number4
DOIs
Publication statusPublished - 2014

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Mucinous Adenocarcinoma
Gene Fusion
Neoplasms
Phosphatidylinositol 3-Kinases
Transcriptome
Epidermal Growth Factor
Agar
Lung Neoplasms
Ligands
Cell Line
Lung
Adenocarcinoma of lung
Therapeutics
Ectopic Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Medicine(all)

Cite this

Fernandez-Cuesta, L., Plenker, D., Osada, H., Sun, R., Menon, R., Leenders, F., ... Thomas, R. K. (2014). CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discovery, 4(4), 415-422. https://doi.org/10.1158/2159-8290.CD-13-0633

CD74-NRG1 fusions in lung adenocarcinoma. / Fernandez-Cuesta, Lynnette; Plenker, Dennis; Osada, Hirotaka; Sun, Ruping; Menon, Roopika; Leenders, Frauke; Ortiz-Cuaran, Sandra; Peifer, Martin; Bos, Marc; Daßler, Juliane; Malchers, Florian; Schöttle, Jakob; Vogel, Wenzel; Dahmen, Ilona; Koker, Mirjam; Ullrich, Roland T.; Wright, Gavin M.; Russell, Prudence A.; Wainer, Zoe; Solomon, Benjamin; Brambilla, Elisabeth; Nagy-Mignotte, Héléne; Moro-Sibilot, Denis; Brambilla, Christian G.; Lantuejoul, Sylvie; Altmüller, Janine; Becker, Christian; Nürnberg, Peter; Heuckmann, Johannes M.; Stoelben, Erich; Petersen, Iver; Clement, Joachim H.; Sänger, Jörg; Muscarella, Lucia A.; la Torre, Annamaria; Fazio, Vito M.; Lahortiga, Idoya; Perera, Timothy; Ogata, Souichi; Parade, Marc; Brehmer, Dirk; Vingron, Martin; Heukamp, Lukas C.; Buettner, Reinhard; Zander, Thomas; Wolf, Jürgen; Perner, Sven; Ansén, Sascha; Haas, Stefan A.; Yatabe, Yasushi; Thomas, Roman K.

In: Cancer Discovery, Vol. 4, No. 4, 2014, p. 415-422.

Research output: Contribution to journalArticle

Fernandez-Cuesta, L, Plenker, D, Osada, H, Sun, R, Menon, R, Leenders, F, Ortiz-Cuaran, S, Peifer, M, Bos, M, Daßler, J, Malchers, F, Schöttle, J, Vogel, W, Dahmen, I, Koker, M, Ullrich, RT, Wright, GM, Russell, PA, Wainer, Z, Solomon, B, Brambilla, E, Nagy-Mignotte, H, Moro-Sibilot, D, Brambilla, CG, Lantuejoul, S, Altmüller, J, Becker, C, Nürnberg, P, Heuckmann, JM, Stoelben, E, Petersen, I, Clement, JH, Sänger, J, Muscarella, LA, la Torre, A, Fazio, VM, Lahortiga, I, Perera, T, Ogata, S, Parade, M, Brehmer, D, Vingron, M, Heukamp, LC, Buettner, R, Zander, T, Wolf, J, Perner, S, Ansén, S, Haas, SA, Yatabe, Y & Thomas, RK 2014, 'CD74-NRG1 fusions in lung adenocarcinoma', Cancer Discovery, vol. 4, no. 4, pp. 415-422. https://doi.org/10.1158/2159-8290.CD-13-0633
Fernandez-Cuesta L, Plenker D, Osada H, Sun R, Menon R, Leenders F et al. CD74-NRG1 fusions in lung adenocarcinoma. Cancer Discovery. 2014;4(4):415-422. https://doi.org/10.1158/2159-8290.CD-13-0633
Fernandez-Cuesta, Lynnette ; Plenker, Dennis ; Osada, Hirotaka ; Sun, Ruping ; Menon, Roopika ; Leenders, Frauke ; Ortiz-Cuaran, Sandra ; Peifer, Martin ; Bos, Marc ; Daßler, Juliane ; Malchers, Florian ; Schöttle, Jakob ; Vogel, Wenzel ; Dahmen, Ilona ; Koker, Mirjam ; Ullrich, Roland T. ; Wright, Gavin M. ; Russell, Prudence A. ; Wainer, Zoe ; Solomon, Benjamin ; Brambilla, Elisabeth ; Nagy-Mignotte, Héléne ; Moro-Sibilot, Denis ; Brambilla, Christian G. ; Lantuejoul, Sylvie ; Altmüller, Janine ; Becker, Christian ; Nürnberg, Peter ; Heuckmann, Johannes M. ; Stoelben, Erich ; Petersen, Iver ; Clement, Joachim H. ; Sänger, Jörg ; Muscarella, Lucia A. ; la Torre, Annamaria ; Fazio, Vito M. ; Lahortiga, Idoya ; Perera, Timothy ; Ogata, Souichi ; Parade, Marc ; Brehmer, Dirk ; Vingron, Martin ; Heukamp, Lukas C. ; Buettner, Reinhard ; Zander, Thomas ; Wolf, Jürgen ; Perner, Sven ; Ansén, Sascha ; Haas, Stefan A. ; Yatabe, Yasushi ; Thomas, Roman K. / CD74-NRG1 fusions in lung adenocarcinoma. In: Cancer Discovery. 2014 ; Vol. 4, No. 4. pp. 415-422.
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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.",
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AU - Fernandez-Cuesta, Lynnette

AU - Plenker, Dennis

AU - Osada, Hirotaka

AU - Sun, Ruping

AU - Menon, Roopika

AU - Leenders, Frauke

AU - Ortiz-Cuaran, Sandra

AU - Peifer, Martin

AU - Bos, Marc

AU - Daßler, Juliane

AU - Malchers, Florian

AU - Schöttle, Jakob

AU - Vogel, Wenzel

AU - Dahmen, Ilona

AU - Koker, Mirjam

AU - Ullrich, Roland T.

AU - Wright, Gavin M.

AU - Russell, Prudence A.

AU - Wainer, Zoe

AU - Solomon, Benjamin

AU - Brambilla, Elisabeth

AU - Nagy-Mignotte, Héléne

AU - Moro-Sibilot, Denis

AU - Brambilla, Christian G.

AU - Lantuejoul, Sylvie

AU - Altmüller, Janine

AU - Becker, Christian

AU - Nürnberg, Peter

AU - Heuckmann, Johannes M.

AU - Stoelben, Erich

AU - Petersen, Iver

AU - Clement, Joachim H.

AU - Sänger, Jörg

AU - Muscarella, Lucia A.

AU - la Torre, Annamaria

AU - Fazio, Vito M.

AU - Lahortiga, Idoya

AU - Perera, Timothy

AU - Ogata, Souichi

AU - Parade, Marc

AU - Brehmer, Dirk

AU - Vingron, Martin

AU - Heukamp, Lukas C.

AU - Buettner, Reinhard

AU - Zander, Thomas

AU - Wolf, Jürgen

AU - Perner, Sven

AU - Ansén, Sascha

AU - Haas, Stefan A.

AU - Yatabe, Yasushi

AU - Thomas, Roman K.

PY - 2014

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AB - 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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EP - 422

JO - Cancer Discovery

JF - Cancer Discovery

SN - 2159-8274

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