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

// Domenico Trombetta 1, * , Paolo Graziano 2, * , Aldo Scarpa 3 , Angelo Sparaneo 1 , Giulio Rossi 4 , Antonio Rossi 5 , Massimo Di Maio 6 , Davide Antonello 3 , Andrea Mafficini 3 , Federico Pio Fabrizio 1 , Maria Carmina Manzorra 1 , Teresa Balsamo 1 , Flavia Centra 1 , Michele Simbolo 3 , Angela Pantalone 1 , Michela Notarangelo 1 , Paola Parente 2 , Maria Cecilia Lucia Dimitri 2 , Antonio Bonfitto 2 , Fabiola Fiordelisi 2 , Clelia Tiziana Storlazzi 7 , Alberto L'Abbate 7 , Marco Taurchini 8 , Evaristo Maiello 5 , Vito Michele Fazio 1 and Lucia Anna Muscarella 1 1 Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy 2 Unit of Pathology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy 3 ARC-NET Research Centre and Department of Diagnostics and Public Health, Section of Pathology, University and Hospital Trust of Verona, Verona, Italy 4 Division of Anatomic Pathology, Regional Hospital Umberto Parini, Aosta, Italy 5 Oncology Department, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy 6 Department of Oncology, University of Turin, A. O. Ordine Mauriziano, Torino, Italy 7 Department of Biology, University of Bari "A. Moro", Bari, Italy 8 Unit of Thoracic-Oncology, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Foggia, Italy * These authors contributed equally to this work Correspondence to: Lucia Anna Muscarella, email: l.muscarella@operapadrepio.it Keywords: NRG1; pErbB3; mucinous adenocarcinoma; lung cancer; target therapy Received: October 26, 2017      Accepted: December 05, 2017      Published: January 03, 2018 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.