BACKGROUND Ten percent of non-small cell lung cancers (NSCLCs) harbor mutations in SMARCA4, the gene encoding the SWI/SNF ATPase BRG1. In preclinical models, BRG1 inactivation increases tumor aggressiveness but enhances sensitivity to drugs that target oxidative phosphorylation and inhibit SMARCA2, EZH2, or CDK4/6. To facilitate translation of preclinical findings into clinical studies exploiting these therapeutic vulnerabilities, we assessed the clinical features of patients with tumors harboring BRG1-inactivating mutations. METHODS Datasets from Massachusetts General Hospital and Foundation Medicine were reviewed to determine the prevalence of SMARCA4-mutant NSCLC and describe its clinicopathologic characteristics. BRG1 expression was evaluated by immunohistochemistry and correlated with SMARCA4 mutations. Treatment outcomes were retrospectively assessed. RESULTS We detected SMARCA4 genomic alterations in 9% (n=117/1,422) and 11% (n=3,188/27,281) of NSCLCs in the institutional and Foundation Medicine datasets, respectively. In both cohorts, truncating mutations comprised over one-third of SMARCA4 alterations. Twenty-nine (45%) of 64 SMARCA4-mutant NSCLCs assessed for BRG1 expression demonstrated loss of expression, most (90%) of which had truncating SMARCA4 mutations. Overall, eighty-four percent (n=26/31) of evaluated NSCLCs with truncating SMARCA4 mutations lacked BRG1 expression. Deficient BRG1 expression was predominantly detected in adenocarcinomas with co-occurring mutations in KRAS, TP53, KEAP1, and STK11. Among patients with BRG1-deficient NSCLC who received first-line platinum doublet chemotherapy (n=11) or chemotherapy plus immunotherapy (n=5), median progression-free survival was 38 and 35 days, respectively. CONCLUSIONS BRG1 deficiency is enriched in NSCLCs with truncating SMARCA4 mutations. Clinical outcomes are poor in this molecular subgroup, highlighting the importance of developing novel strategies to target unique vulnerabilities associated with the BRG1-deficient state.

中文翻译：

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BRG1缺陷型非小细胞肺癌的临床病理特征

背景 10% 的非小细胞肺癌 (NSCLC) 存在 SMARCA4 突变，该基因编码 SWI/SNF ATPase BRG1。在临床前模型中，BRG1 失活会增加肿瘤侵袭性，但会增强对靶向氧化磷酸化和抑制 SMARCA2、EZH2 或 CDK4/6 的药物的敏感性。为了促进将临床前研究结果转化为利用这些治疗弱点的临床研究，我们评估了携带 BRG1 失活突变的肿瘤患者的临床特征。方法回顾了来自马萨诸塞州总医院和 Foundation Medicine 的数据集，以确定 SMARCA4 突变 NSCLC 的患病率并描述其临床病理特征。BRG1 表达通过免疫组织化学评估并与 SMARCA4 突变相关。回顾性评估治疗结果。结果 我们分别在机构和基础医学数据集中 9% (n=117/1,422) 和 11% (n=3,188/27,281) 的 NSCLC 中检测到 SMARCA4 基因组改变。在两个队列中，截断突变占 SMARCA4 改变的三分之一以上。评估 BRG1 表达的 64 例 SMARCA4 突变 NSCLC 中有 29 例 (45%) 表现出表达缺失，其中大部分 (90%) 具有截短的 SMARCA4 突变。总体而言，84% (n=26/31) 具有截断 SMARCA4 突变的评估 NSCLC 缺乏 BRG1 表达。BRG1 表达缺陷主要在 KRAS、TP53、KEAP1 和 STK11 中同时发生突变的腺癌中检测到。在接受一线铂类双药化疗（n=11）或化疗加免疫治疗（n=5）的 BRG1 缺陷型 NSCLC 患者中，中位无进展生存期分别为 38 天和 35 天。结论 BRG1 缺陷在具有截断 SMARCA4 突变的 NSCLC 中富集。该分子亚组的临床结果较差，突出了开发针对与 BRG1 缺陷状态相关的独特脆弱性的新策略的重要性。