Characterizing the molecular and clinical implications of NRG1 fusions in NSCLC through integrated RNA and DNA sequencing analysis.

NRG1 fusions are oncogenic drivers in non-small cell lung cancer (NSCLC), with therapeutic relevance highlighted by the FDA's designation of Zenocutuzumab for NRG1 fusion-positive cases. However, the molecular and clinical features of different NRG1 fusion types remain unclear. We retrospectively analyzed 435 NSCLC patients (78 NRG1 fusion-positive, 357 wild-type) from June 2016 to December 2023, using broad-panel DNA/RNA sequencing to assess mutational profiles, tumor mutation burden (TMB), chromosomal instability scores (CIS), and gene expression. Survival analyses were conducted in our cohort (N = 47) and the TCGA dataset (N = 526). Among NRG1-positive patients, 65.8% harbored recurrent fusion partners (e.g., CD74-NRG1, SLC3A2-NRG1), with CD74-NRG1 most frequent (48.1%). These patients showed fewer EGFR/KRAS mutations and lower TMB and CIS compared to wild-type cases (P < 0.01). The remaining 26 patients had unique singleton fusion partners, including 23 novel events such as CEBPD-NRG1 and BMP1-NRG1. This group exhibited significant enrichment of mutations in genes linked to DNA repair and oncogenic pathways (KRAS, MSH2, FANCI, etc.), affecting Fanconi anemia, mismatch repair, PI3K-AKT, and MAPK pathways (P < 0.01). RNA profiling revealed upregulation of DNAJB1 (P < 0.01) and LMNA (P = 0.02) in the singleton group, both associated with worse overall survival in TCGA (HR = 1.52). No significant difference in progression-free survival was seen following first-line EGFR TKI therapy between uncommon and wild-type groups. Our findings highlight the heterogeneity of NRG1 fusions in NSCLC, revealing novel fusions, unique pathway enrichments, and expression profiles that may inform future personalized treatment strategies.