SMARCA4-deficient undifferentiated malignancies in the digestive system: clinicopathological features and prognostic significance with genomic insights from the TCGA cohort

IF 5.4 2区医学 Q1 ONCOLOGY

The Journal of Pathology Pub Date : 2026-10-04 Epub Date: 2026-08-20 DOI:10.1002/path.70107

Yun-Ran Guo, Chang Liu, Xiao Bai, Ke-Chen Li, Jia-Bao Zhao, Kun Lin, Zi-Ting Zhao, Ji-Xuan Lang, Xiao-Han Li, Qi-Jun Wu, Chun-Dong Zhang

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引用次数: 0

Abstract

Deficiency in SWItch/Sucrose Non-FermenTable (SWI/SNF) related barrier-to-autointegration factor (BAF) chromatin remodeling complex subunit ATPase 4 (SMARCA4) drives aggressive behavior across various undifferentiated malignancies. However, its clinicopathological features, prognostic analysis, and molecular significance in undifferentiated digestive system malignancies, clinically rare and poorly characterized entities, remain incompletely elucidated. This study investigated the clinicopathological characteristics and prognostic significance of a retrospective cohort (n = 43). Immunohistochemistry (IHC) identified SMARCA4 deficiency in 30.2% of undifferentiated malignant tumors of the digestive system. Clinically, SMARCA4 deficiency constituted a significant poor-prognosis predictor, correlating with poorer overall survival [OS; hazard ratio (HR) = 3.054, 95% confidence interval (CI) 1.277–7.306, log-rank p = 0.006] and disease-free survival (DFS; HR = 2.717, 95% CI 1.129–6.539, log-rank p = 0.015), independent of assessed lineage markers or microsatellite status. Integrated analysis of The Cancer Genome Atlas (TCGA) data of digestive system malignancies revealed that SMARCA4-mutated tumors exhibited elevated tumor mutational burden (TMB) and distinct co-mutation patterns. Notably, SMARCA4 mutations significantly co-occurred with multiple potentially actionable therapeutic targets, including receptor tyrosine kinases (ERBB2, ERBB3, MET, and RET), DNA damage response genes (BRCA2), and mismatch repair genes (MLH1, MSH2, MSH6). Collectively, our findings identified SMARCA4 deficiency as a predictor of poor prognoses in digestive system malignancies, suggesting a distinct genomic context that may inform therapeutic stratification, including targeted and immunotherapeutic approaches, by focusing on these high-frequency co-mutated targets. © 2026 The Pathological Society of Great Britain and Ireland.

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消化系统中缺乏smarca4的未分化恶性肿瘤：TCGA队列的临床病理特征和预后意义

开关/蔗糖不可发酵（SWI/SNF）相关的自整合障碍因子（BAF）染色质重塑复合物亚基atp酶4 （SMARCA4）的缺乏驱动各种未分化恶性肿瘤的侵袭性行为。然而，其临床病理特征、预后分析以及在未分化消化系统恶性肿瘤（临床上罕见且特征不明确的实体）中的分子意义仍未完全阐明。本研究调查了回顾性队列（n = 43）的临床病理特征和预后意义。免疫组织化学（IHC）发现，30.2%的消化系统未分化恶性肿瘤缺乏SMARCA4。在临床上，SMARCA4缺乏是一个重要的不良预后预测因子，与较差的总生存期相关[OS；风险比（HR) = 3.054, 95%可信区间（CI） 1.277-7.306, log-rank p = 0.006）和无病生存率（DFS; HR = 2.717, 95% CI 1.129-6.539, log-rank p = 0.015），与评估的谱系标记或微卫星状态无关。对消化系统恶性肿瘤肿瘤基因组图谱（TCGA）数据的综合分析显示，smarca4突变的肿瘤表现出肿瘤突变负担（TMB）升高和不同的共突变模式。值得注意的是，SMARCA4突变显著地与多个潜在可操作的治疗靶点共同发生，包括受体酪氨酸激酶（ERBB2、ERBB3、MET和RET）、DNA损伤反应基因（BRCA2）和错配修复基因（MLH1、MSH2、MSH6）。总的来说，我们的研究结果确定了SMARCA4缺乏症是消化系统恶性肿瘤预后不良的一个预测因素，这表明通过关注这些高频共突变靶点，不同的基因组背景可能为治疗分层提供信息，包括靶向和免疫治疗方法。©2026英国和爱尔兰病理学会。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

The Journal of Pathology 医学-病理学

CiteScore

14.10

自引率

1.40%

发文量

144

审稿时长

3-8 weeks

期刊介绍： The Journal of Pathology aims to serve as a translational bridge between basic biomedical science and clinical medicine with particular emphasis on, but not restricted to, tissue based studies. The main interests of the Journal lie in publishing studies that further our understanding the pathophysiological and pathogenetic mechanisms of human disease. The Journal of Pathology welcomes investigative studies on human tissues, in vitro and in vivo experimental studies, and investigations based on animal models with a clear relevance to human disease, including transgenic systems. As well as original research papers, the Journal seeks to provide rapid publication in a variety of other formats, including editorials, review articles, commentaries and perspectives and other features, both contributed and solicited.