Abstract 4887: Recurrent NRG1 rearrangements in Caucasian pulmonary mucinous adenocarcinoma: results from an Italian multi-center cohort

Abstract

Abstract Invasive Mucinous Adenocarcinoma (IMA) is a rare histotype of lung adenocarcinoma associated with an unfavorable prognosis due to the lack of effective treatment. The NRG1 rearrangement is a new subtype-specific molecular feature of IMA and acts as a strong oncogenic inductor of the aberrant tyrosine kinase activity of ErbB2/ErbB3 heterodimers through PI3K-AKT/MAPK cellular cascades. We recently described for the first time the occurrence of NRG1 rearrangements in 31% of Caucasian lung IMAs and highlighted a strong association between NRG1 rearrangements and ErbB3 activation. Here we extended our lung IMA samples cohort by enrolling a total of 71 patients from three different Italian Centers and collected clinical-pathological information and molecular profile, included the mutational status of KRAS, EGFR and ALK genes. We screened all samples by fluorescent in situ hybridization (FISH) for the detection of putative NRG1 rearrangements and by immunohistochemistry (IHC) for the expression of phosphorylated-ErbB3 (pErbB3) receptor. Finally, we customized a new targeted RNA Custom Panel to detect all 9 NRG1-fusion variants published to date to molecular characterize the NRG1 fusion variants in NRG1 rearranged IMAs. Results showed NRG1 rearrangements in 32% of lung IMAs, displaying both NRG1 FISH split signals and deletions of the 5' portion of the gene. IHC confirmed our previous findings of association between pErbB3 immunoreactivity and NRG1 rearrangements, and the heterogeneity of fluorescent signal distribution and immunostaining along the tissue sections. The CD74-NRG1 remains the most common fusion variant identified in lung IMA samples. Correlation analysis among clinical-pathological data, pErbB3 expression and NRG1 rearrangements are ongoing. Our results confirm the usefulness of IHC/FISH combined approach for NRG1 broken tumors identification and highlight the role of NRG1 rearrangement as master molecular marker of lung IMAs, potentially useful to select patients for the emerging target therapies. Citation Format: Domenico Trombetta, Paolo Graziano, Angelo Sparaneo, Giulio Rossi, Antonio Rossi, Marcello Tiseo, Massimo Di Maio, Federico P. Fabrizio, Maria C. Manzorra, Flavia Centra, Leonarda Di Candia, Marco Audisio, Evaristo Maiello, Vito M. Fazio, Lucia A. Muscarella. Recurrent NRG1 rearrangements in Caucasian pulmonary mucinous adenocarcinoma: results from an Italian multi-center cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4887.