Meiling Zhang1, Qian Wang1, Yan Ding2, Guoqun Wang1, Yunqian Chu1, Xiang He3, Xue Wu2, Yang W Shao4, Kaihua Lu5. 1. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. 2. Translational Medicine Research Institute, Geneseeq Technology, Inc., Toronto, Ontario, Canada. 3. Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. 4. Translational Medicine Research Institute, Geneseeq Technology, Inc., Toronto, Ontario, Canada; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. 5. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, People's Republic of China. Electronic address: lukaihua110@126.com.
Abstract
INTRODUCTION: Lung cancer is the leading cause of cancer-related deaths worldwide. ALK receptor tyrosine kinase gene (ALK) rearrangement has been identified in 3% to 5% of patients with NSCLC. The most common ALK rearrangement is echinoderm microtubule associated protein like 4 (EML4)-ALK, with several variants that can be targeted by the tyrosine kinase inhibitor crizotinib. METHODS: In this study using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel cut-like homeobox 1 gene (CUX1)-ALK fusion gene in a patient with lung adenocarcinoma. The exact CUX1-ALK fusion transcript was determined by RNA sequencing and confirmed by reverse-transcriptase polymerase chain reaction. The oncogenic ability of CUX1-ALK fusion gene was further validated in cells of the line 293T for the activation of anaplastic lymphoma kinase (ALK) self-phosphorylation and downstream signaling pathways. RESULTS: After detection of the CUX1-ALK fusion gene, RNA sequencing analysis of formalin-fixed paraffin-embedded sections from the primary tumor specimen was applied to reveal a 97-nucleotide fragment from CUX1 intron 8 inserted before the nucleotide 53 position in ALK exon 20. Expression of the cut-like homeobox 1-ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including the mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription, and phosphoinositide 3-kinase/AKT signaling pathways, which could all be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib, with a progression-free survival of 20 months. CONCLUSIONS: This study provides the novel finding of a CUX1-ALK fusion gene from a patient with NSCLC that could provide personalized treatment solutions for the maximum benefit to patients with NSCLC.
INTRODUCTION: Lung cancer is the leading cause of cancer-related deaths worldwide. ALK receptor tyrosine kinase gene (ALK) rearrangement has been identified in 3% to 5% of patients with NSCLC. The most common ALK rearrangement is echinoderm microtubule associated protein like 4 (EML4)-ALK, with several variants that can be targeted by the tyrosine kinase inhibitor crizotinib. METHODS: In this study using comprehensive next-generation sequencing targeting 416 pan-cancer genes and introns of 16 genes frequently rearranged in cancer, we identified a novel cut-like homeobox 1 gene (CUX1)-ALK fusion gene in a patient with lung adenocarcinoma. The exact CUX1-ALK fusion transcript was determined by RNA sequencing and confirmed by reverse-transcriptase polymerase chain reaction. The oncogenic ability of CUX1-ALK fusion gene was further validated in cells of the line 293T for the activation of anaplastic lymphoma kinase (ALK) self-phosphorylation and downstream signaling pathways. RESULTS: After detection of the CUX1-ALK fusion gene, RNA sequencing analysis of formalin-fixed paraffin-embedded sections from the primary tumor specimen was applied to reveal a 97-nucleotide fragment from CUX1 intron 8 inserted before the nucleotide 53 position in ALK exon 20. Expression of the cut-like homeobox 1-ALK fusion protein in 293T cells confirmed the self-phosphorylation of the fusion protein and the activation of ALK downstream signaling pathways, including the mitogen-activated protein kinase, Janus kinase-signal transducer and activator of transcription, and phosphoinositide 3-kinase/AKT signaling pathways, which could all be inhibited by the addition of crizotinib. Furthermore, the patient showed a superior response to crizotinib, with a progression-free survival of 20 months. CONCLUSIONS: This study provides the novel finding of a CUX1-ALK fusion gene from a patient with NSCLC that could provide personalized treatment solutions for the maximum benefit to patients with NSCLC.
Authors: Viola W Zhu; Alexa B Schrock; Thangavijayan Bosemani; Bryan S Benn; Siraj M Ali; Sai-Hong Ignatius Ou Journal: Lung Cancer (Auckl) Date: 2018-11-08
Authors: Jun Guo; Junping Shi; Ming Yao; Yi Jin; Dengxiang Liu; Weiling Liu; Kai Wang; Da Jiang Journal: Medicine (Baltimore) Date: 2020-11-06 Impact factor: 1.817