Prevalence and molecular landscape of NRG1 fusions in Japanese solid tumors: a nationwide data analysis using the C-CAT database.

[INTRODUCTION] Neuregulin 1 (NRG1) gene fusions are critical oncogenic drivers that activate the ERBB signaling pathway across various solid tumors. Although targeted therapies for NRG1 fusion-positive cancers are advancing rapidly in clinical settings, their epidemiological and clinicogenomic characteristics remain poorly understood, warranting large-scale investigations.

[METHODS] We performed a retrospective analysis of patients with advanced solid tumors who were registered in the Center for Cancer Genomics and Advanced Therapeutics database of Japan between June 2019 and February 2025. Our evaluation focused on the prevalence of NRG1 fusions, identities of fusion partners, co-occurring genomic alterations, tumor mutational burden, microsatellite instability status, and relevant clinical characteristics.

[RESULTS] Our study included 95,149 patients with advanced solid tumors who underwent comprehensive genomic profiling. Among them, 29 (0.03 %) harbored NRG1 fusions, most frequently in lung cancer (17 of 5,670 cases, 0.30 %). CD74 emerged as the predominant fusion partner, constituting 82.4 % of lung cancers, whereas other solid tumors exhibited a more diverse range of partners. Co-occurring genomic alterations were detected in 20 of 29 patients (69.0 %), with the most frequent alterations found in CDKN2A, CDKN2B, and MTAP. Additionally, pathological examination revealed mucinous adenocarcinoma in 17.6 % of lung cancers associated with NRG1 fusions.

[CONCLUSION] This study confirms that NRG1 fusions are rare but significantly associated with lung cancer and the CD74 fusion partner. Our nationwide analysis represents the most comprehensive assessment of NRG1 fusions in Japanese patients with advanced solid tumors.