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Updated: Jun 8, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Actionable Structural Variant Detection via RNA-NGS and DNA-NGS in Patients With Advanced Non-Small Cell Lung Cancer
Dwight Owen1, Rotem Ben-Shachar2, Josephine Feliciano3
1Ohio State University School of Medicine, Columbus.
Importance:
The National Comprehensive Cancer Network (NCCN) guidelines for non-small cell lung cancer suggest that RNA next-generation sequencing (NGS) may improve the detection of fusions and splicing variants compared with DNA-NGS alone. However, there is limited adoption of RNA-NGS in routine oncology clinical care today.
Objective:
To analyze clinical evidence from a diverse cohort of patients with advanced lung adenocarcinoma and compare the detection of NCCN-recommended actionable structural variants (aSVs; fusions and splicing variants) via concurrent DNA and RNA-NGS vs DNA-NGS alone.
Design, Setting, And Participants:
This multisite, retrospective cohort study examined patients sequenced between February 2021 and October 2023 within the deidentified, Tempus multimodal database, consisting of linked molecular and clinical data. Participants included patients with advanced lung adenocarcinoma and sufficient tissue sample quantities for both RNA-NGS and DNA-NGS testing.
Exposures:
Received results from RNA-NGS and DNA-NGS solid-tissue profiling assays.
Main Outcomes And Measures:
Detection rates of NCCN guideline-based structural variants (ALK, ROS1, RET and NTRK1/2/3 fusions, as well as MET exon 14 skipping splicing alterations) found uniquely by RNA-NGS.
Results:
In the evaluable cohort of 5570 patients, median (IQR) age was 67.8 (61.3-75.4) years, and 2989 patients (53.7%) were female. The prevalence of actionable structural variants detected by either RNA-NGS or DNA-NGS was 8.8% (n = 491), with 86.7% (n = 426) of these detected by DNA-NGS. Concurrent RNA-NGS and DNA-NGS identified 15.3% more patients harboring aSVs compared with DNA-NGS alone (491 vs 426 patients, respectively), including 14.3% more patients harboring actionable fusions (376 vs 329 patients) and 18.6% more patients harboring MET exon 14 skipping alterations (115 vs 97 patients). There was no significant association between the assay used for aSV detection and aSV-targeted therapeutic adoption or clinical outcome. Emerging structural variants (eSVs) were found to have a combined prevalence to be 0.7%, with only 47.5% of eSVs detected by DNA-NGS.
Conclusions And Relevance:
In this cohort study, the detection of structural variants via concurrent RNA-NGS and DNA-NGS was higher across multiple NCCN-guideline recommended biomarkers compared with DNA-NGS alone, suggesting that RNA-NGS should be routinely implemented in the care of patients with advanced NSCLC.
Insights
RNA next-generation sequencing (NGS) combined with DNA-NGS detects more actionable structural variants in advanced non-small cell lung cancer (NSCLC) than DNA-NGS alone. Routine RNA-NGS implementation is suggested for improved NSCLC care.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- National Comprehensive Cancer Network (NCCN) guidelines suggest RNA next-generation sequencing (NGS) may enhance detection of fusions and splicing variants in non-small cell lung cancer (NSCLC).
- Despite recommendations, RNA-NGS adoption in routine oncology clinical care remains limited.
Purpose of the Study:
- To compare the detection of NCCN-recommended actionable structural variants (aSVs) using concurrent DNA and RNA-NGS versus DNA-NGS alone in advanced lung adenocarcinoma.
- To analyze clinical evidence from a diverse patient cohort with advanced lung adenocarcinoma.
Main Methods:
- A multisite, retrospective cohort study of 5570 patients with advanced lung adenocarcinoma.
- Analysis of linked molecular and clinical data from the Tempus multimodal database (February 2021 - October 2023).
- Concurrent DNA and RNA-NGS solid-tissue profiling assays were performed.
Main Results:
- Concurrent RNA-NGS and DNA-NGS identified 15.3% more patients with aSVs compared to DNA-NGS alone.
- This included a 14.3% increase in actionable fusions and an 18.6% increase in MET exon 14 skipping alterations.
- Emerging structural variants (eSVs) showed a 0.7% prevalence, with DNA-NGS alone detecting only 47.5% of them.
Conclusions:
- Concurrent RNA-NGS and DNA-NGS demonstrate superior detection rates for multiple NCCN-recommended biomarkers in advanced NSCLC.
- The findings support the routine implementation of RNA-NGS in the clinical care of advanced NSCLC patients for comprehensive variant detection.
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