Yang Junjie, Feng Jing, Duan Zejun, Liu Xing, Zhang Hongwei, Zhang Mingshan, Ma Zhong, Hu Zejuan, Xiang Lei, Qi Xueling
Department of Pathology, Sanbo Brain Hospital, Capital Medical University, Xiangshan Yikesong 50, Haidian District, Beijing, 100093, China.
Department of Neurosurgery, Capital Medical University, Beijing, 100070, China.
Clin Exp Metastasis. 2025 Mar 21;42(3):20. doi: 10.1007/s10585-025-10337-2.
BRG1 deficiency in patients with lung adenocarcinoma that has metastasized to the brain, termed BRG1-deficient brain metastasis lung adenocarcinoma, is an uncommon event. Prior to this study, these patients had not undergone extensive molecular and (epi)genetic analysis. We report a comprehensive clinical, histopathologic, and molecular assessment of 9 BRG1-deficient brain metastasis lung adenocarcinoma cohort (BRG1-deficient BM cohort) in comparison with a 16 BRG1-retained brain metastasis lung adenocarcinoma cohort (BRG1-retained BM cohort). Patients with BRG1-deficient BM exhibited a significantly increased risk of mortality. Molecular analysis revealed a high prevalence of mutations in SMARCA4 and TP53 genes within this group. DNA methylation molecular diagnostics showed a high rate of genomic instability and a markedly lower DNA methylation age in these patients. Functional enrichment analysis of differentially methylated genes suggested that hypomethylation genes were primarily associated with the negative regulation of neuron differentiation, G protein-coupled receptor signaling pathways, and cell differentiation. Conversely, hypermethylation was linked to the regulation of small GTPase mediated signal transduction, Rho protein signal transduction, DNA damage response, and apoptotic processes. This study investigated a rare subgroup of lung adenocarcinoma patients with brain metastasis characterized by BRG1 deficiency and a poor prognosis. Our study not only provides a comprehensive multi-omic data resource but also provides valuable biological insights into patients. The findings may serve as a valuable reference for the future pathological diagnosis of BRG1-deficient brain metastasis in lung adenocarcinoma patients.
在已发生脑转移的肺腺癌患者中，BRG1缺失（称为BRG1缺失型脑转移肺腺癌）是一种罕见情况。在本研究之前，这些患者尚未接受广泛的分子和（表观）遗传学分析。我们报告了对9例BRG1缺失型脑转移肺腺癌队列（BRG1缺失型BM队列）与16例BRG1保留型脑转移肺腺癌队列（BRG1保留型BM队列）进行的全面临床、组织病理学和分子评估。BRG1缺失型BM患者的死亡风险显著增加。分子分析显示该组中SMARCA4和TP53基因的突变发生率很高。DNA甲基化分子诊断显示这些患者的基因组不稳定性发生率很高，且DNA甲基化年龄明显较低。对差异甲基化基因的功能富集分析表明，低甲基化基因主要与神经元分化的负调控、G蛋白偶联受体信号通路和细胞分化相关。相反，高甲基化与小GTPase介导的信号转导、Rho蛋白信号转导、DNA损伤反应和凋亡过程的调控有关。本研究调查了以BRG1缺失和预后不良为特征的脑转移肺腺癌患者的一个罕见亚组。我们的研究不仅提供了全面的多组学数据资源，还为患者提供了有价值的生物学见解。这些发现可能为未来肺腺癌患者BRG1缺失型脑转移的病理诊断提供有价值的参考。
