Frequent <i>NRG1</i> fusions in Caucasian pulmonary mucinous adenocarcinoma predicted by Phospho-ErbB3 expression

Abstract

<i>NRG1</i> fusions were recently reported as a new molecular feature of Invasive Mucinous Adenocarcinoma (IMA) of the lung. The <i>NRG1</i> 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 <i>NRG1</i> fusions were widely investigated in Asian IMA cohorts, whereas just anecdotal information are available about the occurrence of <i>NRG1</i> 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 <i>KRAS</i>, <i>EGFR</i> and <i>ALK</i> genes. The <i>NRG1</i> rearrangements were detected in 31% IMAs and 3% non-IMAs and the CD74-<i>NRG1</i> fusion transcript variant was characterized in 4 <i>NRG1</i>-positive IMAs. Moreover, pErbB3 expression was found to be strictly associated to the mucinous pattern (<i>p</i> = 0.012, Chi-square test) and all IMA cases showing aberrant expression of pErbB3 demonstrated <i>NRG1</i> rearrangements. No significant correlation between <i>NRG1</i> rearrangements and <i>EGFR</i>, <i>KRAS</i> or <i>ALK</i> mutations respectively, was observed. We report for the first time that <i>NRG1</i> 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 <i>NRG1</i>-positive patients.