NRG1 fusion in a French cohort of invasive mucinous lung adenocarcinoma.

Michaël Duruisseaux,Nathalie Rabbe,Sanaz Alavizadeh,Roger Lacave,Martine Antoine,Anne Mcleer‐Florin,Virginie Poulot,Marie Wislez,Jacques Cadranel

doi:10.1002/cam4.838

Abstract

Invasive mucinous lung adenocarcinoma (IMA) is a rare subtype of lung adenocarcinoma with no effective treatment option in advanced disease. KRAS mutations occur in 28–87% of the cases. NRG1 fusions were recently discovered in KRAS‐negative IMA cases and otherwise negative for known driver oncogenes and could represent an attractive therapeutic target. Published data suggest that NRG1 fusions occur essentially in nonsmoking Asian women. From an IMA cohort of 25 French patients of known ethnicity, driver oncogenes EGFR, KRAS, BRAF, ERBB2 mutations, and ALK and ROS1 rearrangements presence were analyzed. In the IMA samples remaining negative for these driver oncogenes, an NRG1 rearrangement detection was performed by FISH. A driver oncogene was identified in 14/25 IMA, namely 12 KRAS mutations (48%), one ROS1 rearrangement (4%), and one ALK rearrangement (4%). The detection of NRG1 rearrangement by FISH was conducted in the 11 pan‐negative IMA. One sample was NRG1 FISH‐positive and 100% of the tumor nuclei analyzed were positive. This NRG1‐positive patient was a 61‐year‐old nonsmoking woman of Vietnamese ethnicity and was the sole patient of Asian ethnicity of the cohort. She died 6 months after the diagnosis with a pulmonary multifocal disease. NRG1 FISH detection should be considered in patients with IMA pan‐negative for known driver oncogenes. These results might suggest that NRG1 fusion is more frequent in IMA from Asian patient. Larger studies are needed.

Highlights

Invasive mucinous adenocarcinoma (IMA) of the lung represents 2–10% of all lung adenocarcinomas (LUAD)[1,2,3]
NRG1 rearrangements may be found by FISH in IMA wild-type for EGFR, KRAS, BRAF, ERBB2, ALK, and ROS1
Previous works using high throughput transcriptome sequencing in frozen samples or anchored multiplex PCR and next-generation sequencing in formalin-fixed paraffin-embedded (FFPE) samples estimated prevalence for NRG1 fusions in IMA of 7–27% [11,12,13]

Summary

Introduction

Invasive mucinous adenocarcinoma (IMA) of the lung represents 2–10% of all lung adenocarcinomas (LUAD)[1,2,3]. Invasive mucinous adenocarcinoma (IMA) of the lung represents 2–10% of all lung adenocarcinomas (LUAD). Recurrent CD74-NRG1 somatic gene fusions were discovered in IMA cases otherwise negative for known driver oncogenes (EGFR, KRAS, BRAF, ERBB2, ALK, ROS1) [13]. NRG1 (neuregulin 1) is usually not expressed in normal lung and in LUAD, but NRG1 fusions lead to NRG1 III-b3 isoform expression in IMA. The resulting activation of the downstream PI3K-AKT and MAPK pathways promotes anchorage- independent growth of LUAD cell lines. As ERBB2-ERBB3 dimers and PI3K-AKT and MAPK pathways could be targetable, NRG1 fusions represent promising therapeutic targets [14]. NRG1 fusion-m ediated signaling could be effectively suppressed in vitro by tyrosine kinase inhibitors such as lapatinib and afatinib approved for clinical use

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Results

Conclusion