Profiling <i> <i>NRG1</i> </i> fusions in NSCLC: A comparative analysis of DNA+RNA-NGS and DNA-NGS assays.

Abstract

e20742 Background: The neuroregulin 1 ( NRG1 ) gene fusion is a rare but clinically significant target in non-small cell lung cancer (NSCLC). Recently, targeted therapies for NRG1 have been approved and incorporated into clinical guidelines. However, the underdetection of NRG1 fusions at the DNA level remains a considerable challenge. In recent years, DNA+RNA-NGS has been successively recommended in expert consensus documents and clinical guidelines, and has been reported to offer superior performance in detecting fusion genes in NSCLC. This study evaluates the detection rate of NRG1 fusions using DNA+RNA-NGS compared to DNA-NGS in NSCLC patients in a real-world setting, providing reliable evidence for clinical practice. Methods: This study enrolled Chinese NSCLC patients from March 2022 and November 2025. Among them, 5032 patients underwent DNA-NGS, while 11432 patients received DNA+RNA-NGS. The DNA+RNA-NGS approach involved extracting both DNA and RNA from the same tissue sample, with RNA reverse-transcribed into complementary DNA (cDNA) and then combined with DNA. Within a single reaction system, DNA-NGS was employed to identify SNVs/Indels while RNA-NGS targeted fusion genes. NRG1 fusion-positive cases were identified and analyzed separately within each cohort. Results: The results demonstrated a higher NRG1 detection rate in the DNA+RNA-NGS cohort (0.219%) compared to the DNA-NGS cohort (0.099%). Further analysis revealed that 36% (9/25) of patients in the DNA+RNA-NGS cohort harbored at least two NRG1 fusion variants, whereas only single fusions were detected in the DNA-NGS cohort. Among all identified fusion variants (n = 45), CD74 was the most frequent fusion partner (64.44%, 29/45), significantly higher than the 20%-30% reported in the literature, followed by ATP1B1 (17.78%, 8/45). Additionally, DNA+RNA-NGS identified a wider spectrum of fusion partners, while the relatively common partner ATP1B1 was not detected in the DNA-NGS cohort. Further examination of the breakpoints revealed that the NRG1 breakpoints were predominantly located in exon 5. Clinical characteristics analysis indicated that nearly all NRG1 fusion-positive patients were diagnosed with lung adenocarcinoma. Conclusions: In conclusion, DNA+RNA-NGS significantly enhances the detection capability of NRG1 fusions, providing critical insights for precision medicine.