Abstract 3348: Clinical relevance and tumor microenvironment characteristics of SMARCD3 expression in gastric cancer

Abstract Background: SMARCD3, a member of the SWI/SNF family, plays a role in chromatin remodeling and gene transcription. Although its involvement in mesenchymal-epithelial transition in breast cancer cells has been reported, its clinical significance in gastric cancer (GC) remains unclear. This study aims to investigate the clinical relevance of SMARCD3 expression in GC and its impact on the tumor microenvironment, survival outcomes, and tumor biology. Methods: We analyzed clinical and gene expression data from 807 GC patients in The Cancer Genome Atlas (TCGA) and GSE57495 cohorts. SMARCD3 high expression was defined as the top tertile in each cohort. Gene set enrichment analysis (GSEA) was performed to explore biological pathways, while the xCell algorithm was used to evaluate immune and stromal cell infiltration in the tumor microenvironment. Results: High SMARCD3 expression was significantly associated with worse overall survival in both cohorts (p = 0.044, and p = 0.005, respectively), underscoring its potential as a prognostic marker. Tumors with elevated SMARCD3 expression exhibited deeper invasion and more aggressive pathological features (all p < 0.001). SMARCD3-high tumors showed lower tumor mutation burden but higher intratumoral heterogeneity, indicating a complex genomic landscape. Immune profiling of SMARCD3-high GC revealed reduced infiltration of both anti- and pro-tumor immune cells, including CD4+ memory T cells, Th1, Th2, and NK cells (all p < 0.001). Conversely, these tumors demonstrated increased infiltration of stromal cells, including fibroblasts, adipocytes, microvascular endothelial cells, lymphatic endothelial cells, and pericytes (all p < 0.001), reflecting a distinct tumor microenvironment. GSEA revealed significant enrichment of pro-cancerous pathways, including the epithelial-mesenchymal transition, the Hedgehog signaling, the Apical Junction, and Myogenesis, while proliferation-related pathways were inversely correlated with SMARCD3 expression. Conclusions: SMARCD3-high GC is associated with poor prognosis, characterized by aggressive tumor behavior, distinct immune and stromal profiles, and activation of pro-cancerous pathways compared to SMARCD3-low GC. These findings suggest that SMARCD3 is a potential prognostic biomarker, aiding in the stratification of GC patients and informing personalized treatment strategies. Further validation in clinical settings may establish its utility in guiding therapeutic decisions. Citation Format: Kizuki Yuza, Masanori Oshi, Yusuke Takeshita, Tomoaki Takahashi, Sho Sato, Takashi Kosaka, Takafumi Kumamoto, Tsutomu Sato, Kazuaki Takabe, Itaru Endo. Clinical relevance and tumor microenvironment characteristics of SMARCD3 expression in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3348.