Abstract 5369: Characterizing the molecular and clinical implications of<i>NRG1</i>fusions in NSCLC through integrated RNA and DNA sequencing analyses

Abstract Background: NRG1 fusions are oncogenic drivers in NSCLC, with therapeutic implications underscored by FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases. Despite this, the molecular characteristics and clinical impacts of distinct NRG1 fusion types remain poorly understood. Methods: We retrospectively enrolled 435 NSCLC patients, comprising 78 with NRG1 fusions and 357 wild-type (WT), from June 2016 to December 2023. We assessed mutational landscapes, tumor mutation burden (TMB), chromosomal instability scores (CIS), and gene expression using broad-panel targeted DNA and RNA sequencing analyses. Survival analyses were conducted in patients from our cohort (N=47) and online TCGA database (N=526). Results: Among the NRG1 fusion-positive patients, 65.8% harbored recurrent fusion partners like CD74-NRG1 and SLC3A2-NRG1, with CD74-NRG1 appearing most frequently (48.1%). These recurrent fusions were associated with significantly fewer EGFR and KRAS mutations and lower TMB and CIS compared to WT (P &amp;lt; 0.01). Additionally, 26 patients had unique singleton fusion partners, with 23 novel fusions identified, including CEBPD-NRG1 and BMP1-NRG1, although validation through tools such as RNA sequencing is warranted in the future. Interestingly, this group showed significant enrichment of mutations in genes like KRAS, MSH2, MSH6, FANCI, and MDM2, impacting key oncogenic and DNA-repair pathways including Fanconi anemia, mismatch repair, PI3K-AKT, and MAPK pathways (P &amp;lt; 0.01). Additionally, the RNA profiling showed upregulation of DNAJB1 (P &amp;lt; 0.01) and LMNA (P = 0.02) in the singleton group versus WT, linked to poorer overall survival (OS) in the TCGA cohort (HR: 1.52 for both). No significant differences in progression-free survival (PFS) were observed between uncommon and WT groups following the first-line anti-EGFR tyrosine kinase inhibitor (TKI) therapy. Conclusion: This study revealed the diversity of NRG1 fusions in NSCLC, identifying novel fusion partners and distinct molecular and clinical features across novel NRG1+ groups, especially the enriched DNA repair/oncogenic signaling pathways and uniquely upregulated transcription profile. Our study highlights the need of subtyping different NRG+ tumors to better understand their tumorigenesis and facilitates more personalized and targeted treatment of NRG1+ NSCLC patients. Citation Format: Minyi Zhu, Yang Xu, Haimeng Tang, Xue Wu, Qiuxiang Ou. Characterizing the molecular and clinical implications ofNRG1fusions in NSCLC through integrated RNA and DNA sequencing analyses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5369.