8033 Background: SMARCA4 mutations occur in 5–10% of non-small cell lung cancers (NSCLCs) and are associated with poor overall survival, especially class I SMARCA4 alterations (truncating mutations, fusions, and homozygous deletion), which often result in SMARCA4 loss. However, the biological and clinical significance of SMARCA4 alteration classes and their distribution among pan-cancers in Asians remain unclear. Methods: We analyzed pan-cancer across solid tumors patients enrolled in Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database (approval number CDU2021-001N) between June 2019 and October 2025 and patients with surgically resected NSCLCs at our hospital between 1999 and 2023 (approval number 2005-109) were performed by whole exome sequencing. Somatic mutations were annotated using Annovar and OncoKB. SMARCA4 mutations were classified into two groups: class I or class II (missense or other). Copy number alterations were detected using facets and GISTIC2. Transcriptomic differences were assessed using RNA sequencing with DESeq2 and gene set enrichment analysis (GSEA). Tumor immune cell composition was assessed using CIBERSORTx. Results: In the C-CAT pan-cancer dataset (N=10,155), SMARCA4 mutations were frequently identified in NSCLC (NSCLC vs. others; 12.3% vs. 4.0%). In NSCLC, TP53 was the most frequent co-altered gene in patients with class I and class II mutation (73.0% vs. 63.0%). Other major genes did not show clear class-associated differences. In our NSCLC cohort (N=1,166), the frequency of SMARCA4 class I and II mutation was 2.3% (all truncating) and 2.3% (all missense), respectively. The class I SMARCA4 alterations were associated with significantly poorer survival outcomes compared with wild- type tumors (OS: HR = 2.04, 95% CI = 1.24–3.12, p = 0.007; RFS: HR = 2.09, 95% CI = 1.28–3.20, p = 0.005), whereas class II alterations were not significantly different in survival (OS: HR =0.50, 95% CI =0.40-0.61, p =0.17; RFS: HR = 0.46, 95% CI = 0.42–0.76, p =0.12). Regarding transcriptomic analysis and genomic profiling, class I tumors showed activation of ASCL1 -related transcriptional programs, suppression of squamous/basal lineage differentiation, increased CD8⁺ T-cell infiltration, and recurrent copy number loss of SMARCA2 and CDKN2A/B compared with wild type tumors. In contrast, class II tumors showed limited transcriptomic divergence from wild-type tumors, downregulating SPRR2E , KRT5 , and KRT13 without a significant CD8⁺ T-cell difference. Conclusions: In NSCLC, class I SMARCA4 altered tumors are associated with poor survival outcomes, and an immune-active molecular phenotype with recurrent copy number loss of SMARCA2 and CDKN2A/B , whereas class II tumors lack these features and do not show adverse survival compared to wild-type tumors. This highlights the distinct clinical implications of SMARCA4 alteration class.
Takemura et al. (Thu,) studied this question.