Frequent NRG1 fusions in caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression

Domenico Trombetta, Paolo Graziano, Aldo Scarpa, Angelo Sparaneo, Giulio Rossi, Antonio Rossi, Massimo Di Maio, Davide Antonello, Andrea Mafficini, Federico Pio Fabrizio, Maria Carmina Manzorra, Teresa Balsamo, Flavia Centra, Michele Simbolo, Angela Pantalone, Michela Notarangelo, Paola Parente, Maria Cecilia Lucia Dimitri, Antonio Bonfitto, Fabiola FiordelisiClelia Tiziana Storlazzi, Alberto L'Abbate, Marco Taurchini, Evaristo Maiello, Vito Michele Fazio, Lucia Anna Muscarella

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

NRG1 fusions were recently reported as a new molecular feature of Invasive Mucinous Adenocarcinoma (IMA) of the lung. The NRG1 chimeric ligand acts as a strong inductor of phosphorylation and tyrosine kinase activity of the ErbB2/ErbB3 heterodimer, thus enhancing the PI3K-AKT/MAPK pathways. The NRG1 fusions were widely investigated in Asian IMA cohorts, whereas just anecdotal information are available about the occurrence of NRG1 fusions in IMA Caucasian population. Here we firstly explored a large Caucasian cohort of 51 IMAs and 34 non- IMA cases for the occurrence of NRG1 rearrangements by fluorescent in situ hybridization (FISH) and RNA target sequencing. FISH results were correlated to the immunohistochemical expression of phosphorylated-ErbB3 (pErbB3) receptor and the mutational status of KRAS, EGFR and ALK genes. The NRG1 rearrangements were detected in 31% IMAs and 3% non-IMAs and the CD74-NRG1 fusion transcript variant was characterized in 4 NRG1-positive IMAs. Moreover, pErbB3 expression was found to be strictly associated to the mucinous pattern (p = 0.012, Chi-square test) and all IMA cases showing aberrant expression of pErbB3 demonstrated NRG1 rearrangements. No significant correlation between NRG1 rearrangements and EGFR, KRAS or ALK mutations respectively, was observed. We report for the first time that NRG1 fusions are driver alterations clearly associated with mucinous lung adenocarcinoma subtype of Caucasian patients and not exclusive of Asiatic population. pErbB3 immunostaining may represent a strong predictor of NRG1 fusions, pointing out the detection of pErbB3 by IHC as a rapid and effective pre-screening method to select the NRG1-positive patients.

Original languageEnglish
Pages (from-to)9661-9671
Number of pages11
JournalOncotarget
Volume9
Issue number11
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Mucinous Adenocarcinoma
Fluorescence In Situ Hybridization
RNA Sequence Analysis
erbB-1 Genes
Chi-Square Distribution
Phosphatidylinositol 3-Kinases
Protein-Tyrosine Kinases
Population
Adenocarcinoma of lung
Phosphorylation
Ligands
Mutation

Keywords

  • Lung cancer
  • Mucinous adenocarcinoma
  • NRG1
  • PErbB3
  • Target therapy

ASJC Scopus subject areas

  • Oncology

Cite this

Frequent NRG1 fusions in caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression. / Trombetta, Domenico; Graziano, Paolo; Scarpa, Aldo; Sparaneo, Angelo; Rossi, Giulio; Rossi, Antonio; Di Maio, Massimo; Antonello, Davide; Mafficini, Andrea; Fabrizio, Federico Pio; Manzorra, Maria Carmina; Balsamo, Teresa; Centra, Flavia; Simbolo, Michele; Pantalone, Angela; Notarangelo, Michela; Parente, Paola; Dimitri, Maria Cecilia Lucia; Bonfitto, Antonio; Fiordelisi, Fabiola; Storlazzi, Clelia Tiziana; L'Abbate, Alberto; Taurchini, Marco; Maiello, Evaristo; Fazio, Vito Michele; Muscarella, Lucia Anna.

In: Oncotarget, Vol. 9, No. 11, 01.01.2018, p. 9661-9671.

Research output: Contribution to journalArticle

Trombetta, D, Graziano, P, Scarpa, A, Sparaneo, A, Rossi, G, Rossi, A, Di Maio, M, Antonello, D, Mafficini, A, Fabrizio, FP, Manzorra, MC, Balsamo, T, Centra, F, Simbolo, M, Pantalone, A, Notarangelo, M, Parente, P, Dimitri, MCL, Bonfitto, A, Fiordelisi, F, Storlazzi, CT, L'Abbate, A, Taurchini, M, Maiello, E, Fazio, VM & Muscarella, LA 2018, 'Frequent NRG1 fusions in caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression', Oncotarget, vol. 9, no. 11, pp. 9661-9671. https://doi.org/10.18632/oncotarget.23800
Trombetta, Domenico ; Graziano, Paolo ; Scarpa, Aldo ; Sparaneo, Angelo ; Rossi, Giulio ; Rossi, Antonio ; Di Maio, Massimo ; Antonello, Davide ; Mafficini, Andrea ; Fabrizio, Federico Pio ; Manzorra, Maria Carmina ; Balsamo, Teresa ; Centra, Flavia ; Simbolo, Michele ; Pantalone, Angela ; Notarangelo, Michela ; Parente, Paola ; Dimitri, Maria Cecilia Lucia ; Bonfitto, Antonio ; Fiordelisi, Fabiola ; Storlazzi, Clelia Tiziana ; L'Abbate, Alberto ; Taurchini, Marco ; Maiello, Evaristo ; Fazio, Vito Michele ; Muscarella, Lucia Anna. / Frequent NRG1 fusions in caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression. In: Oncotarget. 2018 ; Vol. 9, No. 11. pp. 9661-9671.
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AU - Trombetta, Domenico

AU - Graziano, Paolo

AU - Scarpa, Aldo

AU - Sparaneo, Angelo

AU - Rossi, Giulio

AU - Rossi, Antonio

AU - Di Maio, Massimo

AU - Antonello, Davide

AU - Mafficini, Andrea

AU - Fabrizio, Federico Pio

AU - Manzorra, Maria Carmina

AU - Balsamo, Teresa

AU - Centra, Flavia

AU - Simbolo, Michele

AU - Pantalone, Angela

AU - Notarangelo, Michela

AU - Parente, Paola

AU - Dimitri, Maria Cecilia Lucia

AU - Bonfitto, Antonio

AU - Fiordelisi, Fabiola

AU - Storlazzi, Clelia Tiziana

AU - L'Abbate, Alberto

AU - Taurchini, Marco

AU - Maiello, Evaristo

AU - Fazio, Vito Michele

AU - Muscarella, Lucia Anna

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AB - NRG1 fusions were recently reported as a new molecular feature of Invasive Mucinous Adenocarcinoma (IMA) of the lung. The NRG1 chimeric ligand acts as a strong inductor of phosphorylation and tyrosine kinase activity of the ErbB2/ErbB3 heterodimer, thus enhancing the PI3K-AKT/MAPK pathways. The NRG1 fusions were widely investigated in Asian IMA cohorts, whereas just anecdotal information are available about the occurrence of NRG1 fusions in IMA Caucasian population. Here we firstly explored a large Caucasian cohort of 51 IMAs and 34 non- IMA cases for the occurrence of NRG1 rearrangements by fluorescent in situ hybridization (FISH) and RNA target sequencing. FISH results were correlated to the immunohistochemical expression of phosphorylated-ErbB3 (pErbB3) receptor and the mutational status of KRAS, EGFR and ALK genes. The NRG1 rearrangements were detected in 31% IMAs and 3% non-IMAs and the CD74-NRG1 fusion transcript variant was characterized in 4 NRG1-positive IMAs. Moreover, pErbB3 expression was found to be strictly associated to the mucinous pattern (p = 0.012, Chi-square test) and all IMA cases showing aberrant expression of pErbB3 demonstrated NRG1 rearrangements. No significant correlation between NRG1 rearrangements and EGFR, KRAS or ALK mutations respectively, was observed. We report for the first time that NRG1 fusions are driver alterations clearly associated with mucinous lung adenocarcinoma subtype of Caucasian patients and not exclusive of Asiatic population. pErbB3 immunostaining may represent a strong predictor of NRG1 fusions, pointing out the detection of pErbB3 by IHC as a rapid and effective pre-screening method to select the NRG1-positive patients.

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