[Clinicopathological analysis of SMARCA4-deficient tumors of digestive system origin]

Objective: To analyze the clinicopathological characteristics, treatment, and prognosis of SMARCA4-deficient tumors of digestive system origin, and to deepen the understanding of this tumor subtype. Methods: A retrospective analysis was conducted on 18 patients diagnosed with SMARCA4-deficient tumors of digestive system origin at Tianjin Medical University Cancer Institute and Hospital from January 1, 2021 to December 31, 2024. Their clinicopathological features, treatments, and prognoses were summarized. Immunohistochemical staining was used to detect BRG1. Using solid tumor data from the MSK-CHORD cohort (25 040 samples from 24 950 patients) and the MSK-IMPACT cohort (54 331 samples from 48 179 patients) in the public database cBioPortal, survival analysis and gene mutation profiling were performed focusing on SMARCA4 gene alterations. Results: The 18 SMARCA4-deficient tumors included 10 gastric cancers, 4 gallbladder/bile duct cancers, 2 liver cancers, and 2 colorectal cancers. The mean age of the patients was 62.8 years; there were 14 males and 4 females. Seven patients were initially diagnosed with advanced-stage disease, of whom 5 had metastases to ≥2 distant organs. Based on cytomorphology and immunohistochemistry (IHC) results, 8 cases were classified as undifferentiated carcinoma, 2 as poorly differentiated carcinoma, 5 as poorly differentiated adenocarcinoma, 1 as neuroendocrine carcinoma and 2 as undifferentiated sarcomas. Among the 18 patients, 16 had a Ki-67 index>50%, and high expression levels were observed for INI1 (14/14) and Syn (12/15). Regarding survival, 5 patients had an overall survival (OS) of <6 months, including 3 with stage Ⅱ/Ⅲ disease. Six patients had an OS exceeding 1 year; among them, 4 underwent radical surgery (2 patients with gastric cancer received perioperative immunotherapy combined with chemotherapy), and 2 patients initially diagnosed with advanced-stage disease received immunotherapy combined with chemotherapy, achieving an OS exceeding 17 months and are currently still on maintenance therapy. Database analysis results showed that the frequency of SMARCA4 gene mutations in solid tumors was 5%. Patients without SMARCA4 mutations had better OS than those with SMARCA4 mutations (MSK-CHORD cohort: 50.43 vs 33.24 months, HR=0.743, P<0.001; MSK-IMPACT cohort: 44.05 vs 35.60 months, HR=0.816, P<0.001). Conclusions: SMARCA4-deficient tumors of digestive system origin are poorly differentiated, may present as undifferentiated carcinoma, and some cases show differentiation tendencies toward adenocarcinoma or neuroendocrine carcinoma. These tumors are highly aggressive with poor prognosis. The limited sample size shows a polarized trend in survival data.