Mian Xie1, Shenhai Wei2, Xiaojun Wu3, Xiaoxiang Li4, You You4, Chaosheng He5. 1. Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. Electronic address: mianxie@gird.cn. 2. Department of Thoracic Surgery, First Hospital of Tsinghua University, Beijing, China. 3. Department of Colorectal Surgery, Sun-yet sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Guangzhou, China. 4. Guangzhou Institute of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China. 5. Department of Internal Medicine, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
Abstract
INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
INTRODUCTION: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. METHODS: 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. RESULTS: 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. CONCLUSION: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.
Authors: Sarah Atallah; Morgane Marc; Antoine Schernberg; Florence Huguet; Isabelle Wagner; Antti Mäkitie; Bertrand Baujat Journal: Cancer Manag Res Date: 2022-06-04 Impact factor: 3.602