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

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• NRG1 fusions are key drivers in non-small cell lung cancer (NSCLC).
• Zenocutuzumab is FDA-designated for NRG1 fusion-positive NSCLC.
• Molecular and clinical features of diverse NRG1 fusion types require clarification.

Purpose of the Study:

• To investigate the molecular and clinical characteristics of different NRG1 fusion subtypes in NSCLC.
• To identify novel NRG1 fusions and associated mutational/expression profiles.
• To explore the clinical implications of NRG1 fusion heterogeneity for treatment strategies.

Main Methods:

• Retrospective analysis of 435 NSCLC patients (78 NRG1 fusion-positive, 357 wild-type) from June 2016 to December 2023.
• Broad-panel DNA/RNA sequencing to assess mutational profiles, tumor mutation burden (TMB), chromosomal instability scores (CIS), and gene expression.
• Survival analyses in a cohort and the TCGA dataset.

Main Results:

• Recurrent NRG1 fusions (e.g., CD74-NRG1) were found in 65.8% of fusion-positive cases.
• NRG1 fusion-positive patients had fewer EGFR/KRAS mutations and lower TMB/CIS than wild-type.
• A distinct group with novel singleton NRG1 fusions showed enrichment in DNA repair and oncogenic pathways (e.g., Fanconi anemia, MAPK).
• Upregulation of DNAJB1 and LMNA in the singleton group correlated with worse overall survival.
• No significant difference in progression-free survival with first-line EGFR TKI therapy between uncommon NRG1 fusions and wild-type groups.

Conclusions:

• NRG1 fusions in NSCLC exhibit significant heterogeneity, including novel fusion partners and distinct pathway enrichments.
• Singleton NRG1 fusions are associated with specific molecular alterations and potentially impact survival.
• Understanding NRG1 fusion diversity is crucial for developing personalized therapeutic approaches in NSCLC.