Genomic characterization of SMARCA4 -mutant versus wild-type non–small cell lung cancer in a Chinese population: A large-scale next-generation sequencing study.

8547 Background: SMARCA4 is a core component of the SWI/SNF chromatin remodeling complex and plays a critical role in transcriptional regulation and tumor suppression. SMARCA4 mutations define a biologically aggressive subset of lung cancer; however, their genomic landscape and clinical implications in Chinese patients with non–small cell lung cancer (NSCLC) remain incompletely characterized. This study aimed to comprehensively compare the genomic alteration profiles between SMARCA4-mutant and SMARCA4–wild-type NSCLC to better define distinct molecular subtypes and potential therapeutic implications. Methods: A total of 2,362 Chinese patients with NSCLC underwent comprehensive next-generation sequencing (NGS) using a 733-gene DNA panel. The prevalence and mutation spectrum of SMARCA4 were analyzed. Genomic alteration profiles, including co-occurring mutations, tumor mutational burden (TMB), and microsatellite instability (MSI) status, were systematically compared between SMARCA4-mutant and wild-type tumors. Results: SMARCA4 mutations were identified in 29 of 2,362 patients (1.23%). The mutation spectrum included frameshift (10.34%), nonframeshift (10.34%), nonsynonymous missense (51.72%), stop-gain (24.14%), and synonymous (3.45%) alterations. SMARCA4-mutant tumors exhibited a distinct genomic profile compared with wild-type tumors. Several genes were significantly enriched in the SMARCA4-mutant group, including STK11 (25.0% vs 5.8%, P < 0.001), FAM135B (25.0% vs 8.2%, P = 0.0068), CDH10 (17.9% vs 4.2%, P = 0.0063), and FUBP1 (7.1% vs 0.3%, P = 0.0036), suggesting increased genomic instability and aggressive tumor biology associated with chromatin remodeling dysfunction. In contrast, EGFR mutations were significantly enriched in the SMARCA4–wild-type group (49.1% vs 14.3%, P < 0.001), indicating a strong mutual exclusivity between SMARCA4 alterations and classical EGFR-driven oncogenesis. SMARCA4-mutant tumors also demonstrated a significantly higher tumor mutational burden compared with wild-type tumors (7.8 vs 3.1 muts/Mb, P < 0.0001), whereas no significant difference in MSI status was observed between the two groups. Conclusions: SMARCA4-mutant NSCLC represents a distinct molecular subtype characterized by enrichment of tumor suppressor gene alterations, chromatin remodeling dysfunction, and elevated TMB, while SMARCA4–wild-type tumors are predominantly driven by canonical tyrosine kinase oncogenes such as EGFR. These findings highlight fundamental differences in tumor biology and suggest divergent therapeutic strategies, with SMARCA4-mutant NSCLC potentially benefiting from immunotherapy-oriented approaches rather than traditional targeted therapies.