From the Departments of Pathology (Nambirajan, Bhardwaj, Jain, Singh), All India Institute of Medical Sciences, New Delhi, India.
and Pulmonary Medicine (Mittal), All India Institute of Medical Sciences, New Delhi, India.
Arch Pathol Lab Med. 2021 Jan 1;145(1):90-98. doi: 10.5858/arpa.2019-0633-OA.
CONTEXT.—: Somatic mutations in SMARCA4 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4) gene and/or BRG1 (Brahma-related gene 1) loss identifies a subset of non-small cell lung carcinomas (NSCLCs) lacking alterations in EGFR (epidermal growth factor receptor), ALK (anaplastic lymphoma kinase), and ROS1 (ROS proto-oncogene 1) genes. Preliminary observations suggest responsiveness to immunotherapy and targeted therapies.
OBJECTIVE.—: To study BRG1 loss in NSCLCs and elucidate the clinicopathologic profile of such SMARCA4-deficient NSCLCs.
DESIGN.—: Non-small cell lung carcinomas diagnosed during 6 years were subject to immunohistochemistry for BRG1 and BRM (Brahma). Tumors with BRG1 loss were stained with antibodies against thyroid transcription factor 1 (TTF-1), p40, cytokeratins, hepatocyte paraffin 1 (Hep Par 1), Sal-like protein 4 (SALL4), CD34, SRY-box 2 (SOX2), chromogranin, synaptophysin, p53, integrase interactor 1, ALK, and ROS1. EGFR mutation testing was performed by polymerase chain reaction-based method.
RESULTS.—: Among 100 NSCLCs tested, 4 cases (4%) showed BRG1 loss. The histology ranged from solid adenocarcinomas (n = 1) to large cell/poorly differentiated carcinomas (n = 3) with clear cell cytology in 2 cases. All showed loss/reduction of BRM with variable cytokeratin and SALL4 expression, and were negative for TTF-1, p40, Hep Par 1, ALK, ROS1, and EGFR mutations. CD34 and SOX2 were negative in all 4 cases. Isolated BRM loss was common (21%), distributed across all NSCLC subtypes including squamous cell carcinomas and a hepatoid adenocarcinoma.
CONCLUSIONS.—: BRG1 loss occurs in a subset of TTF-1/p40-negative poorly differentiated NSCLCs. Identification and follow-up will clarify the prognosis, diagnostic criteria, and potential for therapeutic personalization.
SMARCA4（SWI/SNF 相关，基质相关，肌动蛋白依赖性染色质调节剂，亚家族 A，成员 4）基因和/或 BRG1（Brahma 相关基因 1）缺失的体细胞突变鉴定出一组非小细胞肺癌（NSCLCs），这些肺癌缺乏 EGFR（表皮生长因子受体）、ALK（间变性淋巴瘤激酶）和 ROS1（ROS 原癌基因 1）基因的改变。初步观察表明对免疫疗法和靶向治疗有反应。
研究 NSCLCs 中 BRG1 的缺失，并阐明此类 SMARCA4 缺陷型 NSCLCs 的临床病理特征。
在 6 年内诊断的非小细胞肺癌接受 BRG1 和 BRM（Brahma）免疫组织化学染色。BRG1 缺失的肿瘤用甲状腺转录因子 1（TTF-1）、p40、细胞角蛋白、肝细胞石蜡 1（Hep Par 1）、Sal-like 蛋白 4（SALL4）、CD34、SRY 盒 2（SOX2）、嗜铬粒蛋白、突触素、p53、整合酶相互作用蛋白 1、ALK 和 ROS1 抗体染色。通过聚合酶链反应（PCR）方法进行 EGFR 基因突变检测。
在 100 例 NSCLCs 中，有 4 例（4%）出现 BRG1 缺失。组织学范围从实性腺癌（n=1）到大细胞/低分化癌（n=3），其中 2 例具有透明细胞细胞学。所有病例均表现出 BRM 的丢失/减少，伴有不同程度的细胞角蛋白和 SALL4 表达，并对 TTF-1、p40、Hep Par 1、ALK、ROS1 和 EGFR 突变呈阴性。所有 4 例 CD34 和 SOX2 均为阴性。孤立的 BRM 缺失很常见（21%），分布于所有 NSCLC 亚型，包括鳞状细胞癌和肝样腺癌。
TTF-1/p40 阴性的低分化 NSCLCs 中存在 BRG1 缺失。鉴定和随访将阐明预后、诊断标准以及个性化治疗的潜力。
