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10.3779/j.issn.1009-3419.2024.102.32 ·综述 ·  \nSMARCA4突变非小细胞肺癌研究进展  \n彭丽珊 钟文昭  \n【摘要】非小细胞肺癌（non-small cell lung cancer, NSCLC）是全球发生率和死亡率最高的癌症之一。尽管精准治疗模式下靶向药物及免疫药物的应用改善了患者的预后，但仍有患者无法从中获益，因此探索耐药原因及机制具有重要意义。生存分析发现SMARCA4突变NSCLC患者预后不佳。SMARCA4是SWI/SNF染色体重塑复合物中具有 ATP酶活性的核心亚基，SWI/SNF复合体通过改变染色质可及性调控基因转录，影响分化、细胞周期调控等重要细胞活动，被认为具有抑癌作用。本文将综合阐述SMARCA4突变在肿瘤发生发展过程中的作用以及其在NSCLC中的临床病理特点、治疗预后及潜在治疗方案。  \n【关键词】 肺肿瘤； SMARCA4； SWI/SNF；免疫治疗；合成致死  \nResearch Progress on SMARCA4 Mutation Non-small Cell Lung Cancer  \nLishan PENG, Wenzhao ZHONG  \nGuangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou 510080, China  \nCorresponding author: Wenzhao ZHONG, [E-mail: syzhongwenzhao@scut.edu.cn](E-mail: syzhongwenzhao@scut.edu.cn)  \n【Abstract】 Non-small cell lung cancer (NSCLC) is one of the most prevalent and deadliest cancers worldwide.  \nWhile the use of targeted therapies and immunotherapies in precision medicine has improved outcomes for some patients, a significant portion of individuals still fail to benefit, emphasizing the need to investigate the underlying mechanisms of resistance. Survival analyses have shown that NSCLC patients with SMARCA4 mutations often have poor prognoses. SMARCA4, the core ATPase subunit of the SWI/SNF chromatin remodeling complex, plays a critical role in regulating gene transcription by modifying chromatin accessibility. This influences essential cellular processes such as differentiation and cell cycle regulation, and SMARCA4 is widely regarded as a tumor suppressor. This review will explore the role of SMARCA4 mutations in tumor progression, its clinicopathological features in NSCLC, its impact on treatment outcomes, and potential therapeutic strategies.  \n【Keywords】 Lung neoplasms; SMARCA4; SWI/SNF; Immunotherapy; Synthetic lethality  \n【Copyright statement】 Copyright © 2024, Chinese Journal of Lung Cancer.  \nThis paper was supported by the grants from National Natural Science Foundation of China's Key Scientific Issues on Lung Cancer Major Joint Special Fund (No.82241235), National Health Commission's Medical and Health Technology Development Research Center Fund (No.WKZX2023YG0401), Guangdong Provincial Science and Technology Department's Key Laboratory Construction Project Fund (No.2017B030314120) and National High-level Talent Special Support Program's 2022 Special Support Fund for Selected Talents (No.KA0120231004) (All toWenzhao ZHONG).  \n肺癌具有高发病率和死亡率，2022年全球共有250万新发肺癌患者，其中80%为非小细胞肺癌（non-small cell  \n本文受国家自然科学基金肺癌关键科学问题重大联合专项基金（No. 8 2 2 4 1 2 3 5）、 国家卫健委医药卫生科技发展研究中心基金（No.WK ZX2023YG0401）、广东省科技厅重点实验室建设项目基金（No. 2017B030314120）及国家高层次人才特殊支持计划入选人才2022 年特殊支持经费（No.KA0120231004）资助  \n作者单位：5 1 0 0 8 0 广州，广东省肺癌研究所，南方医科大学广东  \n省人民医院（广东省医学科学院） （通信作者：钟文昭， E-mail : [syzhongwenzhao@scut.edu.cn](syzhongwenzhao@scut.edu.cn)）  \nlung cancer, NSCLC），并有180万人因肺癌死亡[1]。近年来，驱动基因研究的深入以及靶向和免疫治疗等药物的使用，推动了基于分期、病理、基因突变检测的精准治疗模式形成，改善了患者的预后，但仍有患者面临早期复发和疾病进展。因此伴随基因在疾病发展及治疗中的作用受到日益关注，准确了解不同基因突变在肺癌中的特点及致癌机制对于精准治疗具有重要意义。而SM ARCA4就是其中一个重要的伴随基因，SM ARCA4基因作为SWI/SNF染色体重塑复合物的核心催化亚基，其突变失活会改变染色质可及性并影响基因的转录调控，形成具有侵袭性的表型，并且  \n中国肺癌杂志2 0 2 4年9月第2 7卷第9期 Chin J Lung Cancer, September 2 0 2 4 , Vol. 2 7 , No. 9  ·705 ·  \n与不良预后相关[2]。本文综述了SM ARCA4突变的机制以及 2 SMARCA4突变NSCLC的特征  \n其在NSCLC中的特点、治疗及未来展望。  \n1 SMARCA4基因与SWI/SNF复合物  \nSM ARCA4基因位于19号染色体，编码具有7个结构域的BRG1蛋白，是组成SWI/SNF染色体重塑复合物的核心亚基[3]。染色质重塑在基因表达调控中起到重要作用。 SWI/SNF复合物识别特定染色质区域后通过ATP酶水解获得能量滑动或移除核小体，展开染色质，招募转录因子并作用于启动子[4]和增强子[5]，促进转录启动，进而在细胞周期调节[6]、细胞分化[7]等生物过程中发挥作用，并且被认为是抑癌因子。SWI/SNF复合物还能促进DNA同源重组修复[8]，参与DNA损伤位点的核苷酸切除修复[9]。SWI/ SNF复合物这一识别-调节-驱动的染色质重塑过程需要多个亚基协同参与，在哺乳动物中不同亚基组装形成多种不同亚家族，而BRG1是其中核心亚基，不仅编码驱动模块的 ATP酶，SM ARCA4内结构域还与其他亚基一起参与识别及调节模块功能[3]。因此，当SM ARCA4基因发生突变时，可以通过影响ATP酶活性或染色质识别结合功能，进而影响转录及DNA损伤修复[3]，并与肿瘤的发生发展相关。在转录调节方面，研究[10]证明SM ARCA4缺失直接导致所有三类SWI/SNF复合物在调节区域结合和打开染色质的能力缺陷，导致肺谱系转录因子结合的染色质可及性降低。另一方面，SWI/SNF复合物参与组蛋白修饰，与转录抑制因子多梳蛋白抑制复合物","cbCaiaP4voCjVDwW","https://ap.wps.com/l/cbCaiaP4voCjVDwW","pdf",1163793,"Chinese","en","# 摘要\n# 关键词\n# 1 SMARCA4基因与SWI/SNF复合物\n# 2 SMARCA4突变NSCLC的临床病理与分子学特征\n## 2.1 SMARCA4突变NSCLC临床病理特征\n## 2.2 SMARCA4突变NSCLC分子学特征","[{\"question\":\"为什么需要研究SMARCA4突变相关的非小细胞肺癌耐药机制？\",\"answer\":\"精准治疗虽然改善了部分患者预后，但仍有患者无法获益，因此需要探索耐药原因及其机制。文中指出SMARCA4突变与不良预后相关，提示其可能参与耐药相关过程。\"},{\"question\":\"SMARCA4在SWI/SNF染色体重塑复合物中发挥什么作用？\",\"answer\":\"SMARCA4是SWI/SNF复合物中具有ATP酶活性的核心亚基。复合物可改变染色质可及性并调控基因转录，影响分化、细胞周期等生物学过程，并参与DNA损伤修复。\"},{\"question\":\"SMARCA4突变NSCLC在临床病理方面有哪些主要特征？\",\"answer\":\"文中提到SMARCA4突变可通过高通量测序检测，比例为5%到10%。突变使肿瘤更具侵袭性，确诊时远处转移比例更高；同时去分化状态在缺失相关的亚组中更显著。\"}]","SMARCA4突变非小细胞肺癌研究进展 | PDF",1790036200,18]