FrequentNRG1fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression

NRG1fusions were recently reported as a new molecular feature of Invasive Mucinous Adenocarcinoma (IMA) of the lung. TheNRG1chimeric ligand acts as a strong inductor of phosphorylation and tyrosine kinase activity of the ErbB2/ErbB3 heterodimer, thus enhancing the PI3K-AKT/MAPK pathways. TheNRG1fusions were widely investigated in Asian IMA cohorts, whereas just anecdotal information are available about the occurrence ofNRG1fusions 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 ofKRAS,EGFRandALKgenes. TheNRG1rearrangements were detected in 31% IMAs and 3% non-IMAs and the CD74-NRG1fusion transcript variant was characterized in 4NRG1-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 demonstratedNRG1rearrangements. No significant correlation betweenNRG1rearrangements andEGFR,KRASorALKmutations respectively, was observed. We report for the first time thatNRG1fusions 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 theNRG1-positive patients.