Detection of Novel NRG1, EGFR, and MET Fusions in Lung Adenocarcinomas in the Chinese Population

Abstract

Introduction: Multiple oncogene fusions beyond ALK receptor tyrosine kinase (ALK), RET, and ROS1 fusion has been described in lung cancer, especially in lung adenocarcinomas without common oncogenic mutations. Molecular inhibitors have been developed and proved effective for patients whose tumors harbor these novel alterations. Methods: A consecutive series of surgically resected lung adenocarcinomas were collected and profiled using an enrichment strategy to detect nine common oncogenic driver mutations and fusions concerning EGFR, KRAS, HER2, BRAF, MET, ALK, RET, ROS1, and FGFR. Driver-negative cases were further analyzed by a comprehensive RNA-based nextgeneration sequencing (NGS) fusion assay for novel fusions. Results: In total, we profiled 1681 lung adenocarcinomas, among which 255 cases were common driver-negative. One hundred seventy-seven cases had sufficient tissue for NGS fusions screening, which identified eight novel fusions. NRG1 fusions occurred in 0.36% of all lung adenocarcinoma cases (6 of 1681 cases), including 4 CD74-NRG1-positive cases, 1 RBPMS-NRG1-positive case, and 1 novel ITGB1-NRG1-positive case. Furthermore, another 2 novel fusions were also detected, including 1 EGFR-SHC1 fusion and 1 CD47-MET fusion, both of which were in-frame and retained the functional domain of the corresponding kinases. No fusion event was detected for NTRK, KRAS, BRAF or HER2 genes in this cohort. Detailed clinicopathologic data showed that invasive mucous adenocarcinoma (three of eight cases) and acinar-predominant adenocarcinoma (three of eight cases) were the most prevalent pathologic subtypes among novel fusions. Conclusions: Fusions affecting NRG1, EGFR, and MET were detected in 0.48% of unselected lung adenocarcinomas, and NRG1 fusions ranked the most prevalent fusions in common driver-negative lung adenocarcinomas from Chinese population. RNA-based NGS fusion assay was an optional method for screening actionable fusions in common driver-negative cases.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis

“…However, this emphasizes the dynamic NSCLC treatment landscape, and the need for diagnostic molecular profiling panels to continually evolve. The use of RNA based NGS assays with the ability to detect novel fusions may overcome some of these limitations [29], although this may potentially increase the costs of testing. Similarly, guidelines must demonstrate flexibility to incorporate new findings, as illustrated by the absence of any recommendations for these novel targets in guidelines released as recently as 2018 [6].…”

Clinical Characteristics and Risk of Second Primary Lung Cancer After Cervix Cancer: A Population-Based Study

“…Finally, our study has several limitations including notably the lack of biological data including PD-L1 status [24][25][26] . We failed to collect this crucial data as biomarker analysis has not been universalized in clinical practice until very recent years.…”

Clinical characteristics and risk of second primary lung cancer after cervical cancer: A population-based study

“…Finally, the present study had several limitations, including the lack of biological data on the PD-L1 (programmed cell death-1) status [24][25][26]. This crucial data could not be collected because biomarker analysis was not universalized in clinical practice until very recent years.…”