Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
Department of Thoracic Surgery, First Hospital of Tsinghua University, Beijing, China.
Lung Cancer. 2018 Jul;121:41-47. doi: 10.1016/j.lungcan.2018.04.020. Epub 2018 Apr 30.
Adenoid cystic carcinoma (ACC) of the trachea lacks of well-characterized molecular markers. There is currently no specific treatment for metastatic ACC of the trachea. This study aimed to identify genomic mutations of Notch pathway and investigate the efficacy of NOTCH inhibitor in ACC of the trachea.
73 Patients with ACC of the trachea at four institutions from 2008 to 2016 were identified. Analysis of hotspot mutations in cancer-related genes of Notch pathway was performed using next generation sequencing. Gene-expression and functional analyses were performed to study the mechanism of activation through mutation. Univariable and multivariable Cox regression models were used to predict overall survival (OS). Patient-derived xenograft (PDX) models were established and treated with NOTCH inhibitor Brontictuzumab.
Gain-of-function mutations of the NOTCH1 gene occurred in 12 (16.4%) tumors, leading to stabilization of the intracellular cleaved form of NOTCH1 (ICN1). NOTCH1 mutation was associated with increased NOTCH1 activation and its target gene HES1. Mutations in NOTCH2 (3/73), NOTCH4 (2/73), JAG1 (1/73) and FBXW7 (2/73) were also identified in 8 (11.0%) patients. A strong inverse correlation of expression was observed between FBXW7 and HES1. NOTCH1 mutation was associated with solid subtype (P = 0.02), younger age at diagnosis (P = 0.041) and shorter overall survival (OS) (P = 0.017). NOTCH1 mutation was not an independent prognostic factor in the presence of histologic subtype and resection margin. Brontictuzumab significantly reduced tumor growth in NOTCH1-mutated PDX.
NOTCH1 mutation is associated with activation of Notch pathway in ACC of the trachea. NOTCH1 is a potential target for therapeutic intervention in patients with ACC of the trachea.
气管腺样囊性癌（ACC）缺乏特征性的分子标志物。目前对于气管转移性 ACC 尚无特定的治疗方法。本研究旨在鉴定 Notch 通路的基因组突变，并研究 Notch 抑制剂在气管 ACC 中的疗效。
从 2008 年至 2016 年，在四个机构共确定了 73 例气管 ACC 患者。使用下一代测序技术分析 Notch 通路中癌症相关基因的热点突变。进行基因表达和功能分析以研究通过突变激活的机制。采用单变量和多变量 Cox 回归模型预测总生存期（OS）。建立患者来源的异种移植（PDX）模型并使用 Notch 抑制剂 Brontictuzumab 进行治疗。
12 例（16.4%）肿瘤存在 NOTCH1 基因的功能获得性突变，导致 Notch1 细胞内裂解形式（ICN1）的稳定。NOTCH1 突变与 NOTCH1 激活及其靶基因 HES1 的增加相关。还在 8 例（11.0%）患者中鉴定出 NOTCH2（3/73）、NOTCH4（2/73）、JAG1（1/73）和 FBXW7（2/73）的突变。FBXW7 与 HES1 的表达呈强烈的负相关。NOTCH1 突变与实体亚型相关（P=0.02），诊断时年龄较小（P=0.041），总生存期（OS）较短（P=0.017）。在组织学亚型和切缘存在的情况下，NOTCH1 突变不是独立的预后因素。Brontictuzumab 显著抑制了 NOTCH1 突变的 PDX 肿瘤的生长。
NOTCH1 突变与气管 ACC 中 Notch 通路的激活相关。NOTCH1 是气管 ACC 患者治疗干预的潜在靶点。
