Data from <i>CD74–NRG1</i> Fusions in Lung Adenocarcinoma

Abstract

<div>Abstract<p>We discovered a novel somatic gene fusion, <i>CD74–NRG1</i>, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74–NRG1 leads to extracellular expression of the EGF-like domain of NRG1 III-β3, thereby providing the ligand for ERBB2–ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (<i>P</i> < 0.0001). Ectopic expression of CD74–NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K–AKT pathway, and led to increased colony formation in soft agar. Thus, <i>CD74–NRG1</i> gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment.</p><p><b>Significance:</b> <i>CD74–NRG1</i> fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. <i>Cancer Discov; 4(4); 415–22. ©2014 AACR</i>.</p><p>This article is highlighted in the In This Issue feature, p. 377</p></div>