Fluorescent In Situ Hybridization Testing Allows the Diagnosis of <i>NRG1</i> Gene Fusions in Lung and Pancreas Cancers with No Other Identified Oncogenic Driver

Some pancreatic ductal-type (PDADK) and lung adenocarcinomas (LADK) lacking other molecular drivers are reported to harbor <i>NRG1</i> fusions as potential novel therapeutic targets. We investigated the feasibility of a fluorescent in situ hybridization (FISH)-based diagnosis of <i>NRG1</i> fusions in a case series of PDADK and LADK lacking other identified oncogenic drivers. First, among a case series of PDADK, <i>KRAS</i> analyses (PCR followed in PCR-negative cases by RNA sequencing-RNAseq) found 27/162 (16.7%) <i>KRAS</i> wild-type cases, among which 1/162 (0.6%) <i>NRG1</i> fusion was diagnosed using FISH. Secondly, among a case series of LDAK, 191/446 (42.8%) cases had no molecular alterations in <i>EGFR</i>, <i>KRAS</i>, <i>BRAF</i>, <i>HER2</i>, <i>MET</i>, <i>ALK</i>, <i>ROS1</i> and <i>RET</i> according to NGS and FISH analyses and, among them, 4/446 (0.9%) cases had <i>NRG1</i> fusions using FISH. Finally, four additional cases out of the two previously mentioned cases series (1 PDADK and 3 LADK) with <i>NRG1</i> fusions diagnosed by first-line RNAseq were also concluded as <i>NRG1</i> FISH-positive. The <i>NRG1</i> FISH tests for the nine <i>NRG1</i> FISH-positive cases resulted in 50% to 80% of positive tumor nuclei, all with single 3'-<i>NRG1</i> FISH signals. In our series, of the 22 cases analyzed with both <i>NRG1</i> FISH (positivity criterion of at least 15% of tumor nuclei with a split between the 5'- and the 3'- parts of the probes and/or isolated single 3'-<i>NRG1</i> signal) and RNAseq, 17 cases were FISH- RNAseq- and 5 cases were FISH+ RNAseq+ (no FISH+ RNAseq- or FISH- RNAseq+ cases in our study) resulting in 100% sensibility and specificity for the <i>NRG1</i> FISH test. In the case of no access to RNAseq, <i>NRG1</i> FISH consists of a valuable tool searching for <i>NRG1</i> fusions in patients with advanced cancers.