Jia Qiqi, Chen Yishan, Pan Yuyao, Gao Shan, Wei Xiaoyun, Fan Yangyang, Li Pengjun, Yang Zhe, Pu Jun, Nan Pengfei, Chang Hongyun, Zheng Jianyun, Zhang Guanjun, Liu Xi
Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, No. 277 Yanta West Road, Xi'an 710061, Shaanxi, China.
Department of Pathology, Yulin Hospital of Traditional Chinese Medicine, No. 131 Xinjian South Road, Yulin 719099, Shaanxi, China.
Mod Pathol. 2025 Aug 9:100868. doi: 10.1016/j.modpat.2025.100868.
As a key subunit of the SWI/SNF chromatin-remodeling complex, SMARCA4 plays a critical role as a tumor suppressor in various tumors. However, the clinicopathological and molecular features of SMARCA4-deficient carcinoma of the gallbladder (SMARCA4-dGBC) have not been well explored. In this study, a retrospective cohort of 926 non-squamous cell gallbladder carcinomas (GBCs) was analyzed on tissue microarrays using immunohistochemistry for SMARCA4, comprising 813 adenocarcinomas, 53 adenosquamous carcinomas, 43 undifferentiated carcinomas, 7 sarcomatoid carcinomas, 6 small cell neuroendocrine carcinomas, and four large cell neuroendocrine carcinomas. Twenty-six (2.8%) SMARCA4-dGBCs were identified and further analyzed using immunohistochemistry, whole-exome sequencing, and clinicopathological data. SMARCA4-dGBCs are frequently identified in advanced stages and exhibit diverse patterns of differentiation. The majority were identified as monotonous diffuse sheets, nests, and cords, while a subset exhibited gland-forming and rhabdoid morphologies (11.5%). Tumors retained mismatch repair proficiency (100%), but showed variable HER2 expression (11.5% scored as 2+/3+) and limited PD-L1 positivity. Genomic profiling revealed SMARCA4 alterations in 88.5% (23/26) of patients, predominantly deletions (91.3%) and truncating mutations-p.K892* and p.R979*-that disrupt the critical ATPase/helicase domains. Co-occurring TP53 mutations (56.5%) highlighted the presence of synergistic chromatin-remodeling defects. Enrichment of oncogenic signaling pathways, including the RTK-RAS (78.3%), TP53 (60.9%), NOTCH (47.8%), and HIPPO (39.1%) pathways, was observed. Patients with SMARCA4-dGBC exhibited significantly shorter progression-free survival (median, 6 vs. 14 months) and overall survival (median, 11 vs. 16 months) than those with SMARCA4-retained tumors. Overall, these findings revealed that SMARCA4-dGBC is a rare, distinct entity characterized by the destabilization of the SWI/SNF complex, genomic instability, and resistance to conventional therapies. The prevalence of targetable pathways, such as RTK-RAS and cell cycle dysregulation, highlights opportunities for precise therapeutic strategies involving EZH2, CDK4/6, or ATR inhibitors. SMARCA4 immunohistochemistry and molecular profiling are essential for accurate diagnosis, prognostic stratification, and therapeutic innovation of this GBC subtype.
作为SWI/SNF染色质重塑复合体的关键亚基，SMARCA4在多种肿瘤中作为肿瘤抑制因子发挥着关键作用。然而，SMARCA4缺陷型胆囊癌（SMARCA4-dGBC）的临床病理和分子特征尚未得到充分研究。在本研究中，对926例非鳞状细胞胆囊癌（GBC）的回顾性队列进行了分析，在组织芯片上使用免疫组织化学检测SMARCA4，其中包括813例腺癌、53例腺鳞癌、43例未分化癌、7例肉瘤样癌、6例小细胞神经内分泌癌和4例大细胞神经内分泌癌。共鉴定出26例（2.8%）SMARCA4-dGBC，并使用免疫组织化学、全外显子测序和临床病理数据进行进一步分析。SMARCA4-dGBC在晚期阶段经常被发现，并表现出多种分化模式。大多数被鉴定为单调的弥漫性片状、巢状和条索状，而一小部分表现出腺形成和横纹肌样形态（11.5%）。肿瘤保留错配修复能力（100%），但HER2表达可变（11.5%评分为2+/3+），PD-L1阳性率有限。基因组分析显示，88.5%（23/26）的患者存在SMARCA4改变，主要为缺失（91.3%）和截断突变-p.K892和p.R979，这些突变破坏了关键的ATP酶/解旋酶结构域。同时发生的TP53突变（56.5%）突出了协同染色质重塑缺陷的存在。观察到致癌信号通路的富集，包括RTK-RAS（78.3%）、TP53（60.9%）、NOTCH（47.8%）和HIPPO（39.1%）通路。与保留SMARCA4的肿瘤患者相比，SMARCA4-dGBC患者的无进展生存期（中位数，6个月对14个月）和总生存期（中位数，11个月对16个月）明显缩短。总体而言，这些发现表明，SMARCA4-dGBC是一种罕见的、独特的实体，其特征是SWI/SNF复合体不稳定、基因组不稳定以及对传统疗法耐药。可靶向通路的普遍性，如RTK-RAS和细胞周期失调，突出了涉及EZH2、CDK4/6或ATR抑制剂的精确治疗策略的机会。SMARCA4免疫组织化学和分子分析对于这种GBC亚型的准确诊断、预后分层和治疗创新至关重要。
