Xiao-Dong Jiao1, Xiao-Chun Zhang2, Bao-Dong Qin1, Dong Liu2, Liang Liu3, Jian-Jiao Ni3, Zhou-Yu Ning4, Ling-Xiang Chen5, Liang-Jun Zhu5, Song-Bing Qin6, Shen-Peng Ying7, Xue-Qin Chen8, Ai-Jun Li9, Ting Hou10, Han Han-Zhang10, Junyi Ye10, Jingjing Zheng10, Shannon Chuai10, Yuan-Sheng Zang1. 1. Department of Medical Oncology, Changzheng Hospital, Second Military Medical University, Shanghai, China. 2. Department of Medical Oncology, The Affiliated Hospital of Qingdao University, Qingdao University, Qingdao, China. 3. Departments of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. 4. Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. 5. Department of Internal Medicine, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China. 6. Department of Tumor Radiotherapy, The First Affiliated Hospital of Suzhou University, Suzhou, China. 7. Department of Radiotherapy, Taizhou Central Hospital, Taizhou University Hospital, Taizhou, China. 8. Department of Thoracic Oncology, Key Laboratory of Clinical Cancer Pharmacology and Toxicology Research of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. 9. Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. 10. Burning Rock Biotech, Guangzhou, China.
Abstract
BACKGROUND: Tumor mutation burden (TMB) has an important association with immunotherapy responses. TMB in the Chinese population has not been well established. Finding differences between the Chinese and Caucasian populations and elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. METHODS: Chinese cancer patients fresh tissue (n=2,177), formalin-fixed, paraffin-embed (FFPE) specimens (n=3,294), and pleural fluid (n=189) were profiled using a 295- or 520-gene next-generation sequencing (NGS) panel. The association of the TMB status with a series of molecular features and biological pathways was determined using bootstrapping. RESULTS: TMB, measured by 295- or 520-cancer-related gene panels, was correlated with whole-exome sequencing (WES) TMB based on the in silico simulation in The Cancer Genome Atlas cohort. The median TMB of our data was slightly higher than that from the Foundation Medicine Inc. (FMI) dataset. TMB was also slightly different within the same cancer type between the Chinese and Caucasian population. We discovered that the underlying pathways of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 23-gene and a 16-gene signature to predict TMB prediction for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively, indicating a histology-specific mechanism for driving high-TMB in lung cancer. CONCLUSIONS: TMB varies among different ethnic populations. Our findings extend the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types. 2020 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Tumor mutation burden (TMB) has an important association with immunotherapy responses. TMB in the Chinese population has not been well established. Finding differences between the Chinese and Caucasian populations and elucidating the underlying biological mechanisms of high TMB might help develop more precise and effective means for TMB and immunotherapy response prediction. METHODS: Chinese cancer patients fresh tissue (n=2,177), formalin-fixed, paraffin-embed (FFPE) specimens (n=3,294), and pleural fluid (n=189) were profiled using a 295- or 520-gene next-generation sequencing (NGS) panel. The association of the TMB status with a series of molecular features and biological pathways was determined using bootstrapping. RESULTS: TMB, measured by 295- or 520-cancer-related gene panels, was correlated with whole-exome sequencing (WES) TMB based on the in silico simulation in The Cancer Genome Atlas cohort. The median TMB of our data was slightly higher than that from the Foundation Medicine Inc. (FMI) dataset. TMB was also slightly different within the same cancer type between the Chinese and Caucasian population. We discovered that the underlying pathways of TMB status varied greatly and sometimes had an opposite association with TMB across different cancer types. Moreover, we developed a 23-gene and a 16-gene signature to predict TMB prediction for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively, indicating a histology-specific mechanism for driving high-TMB in lung cancer. CONCLUSIONS: TMB varies among different ethnic populations. Our findings extend the knowledge of the underlying biological mechanisms for high TMB and might be helpful for developing more precise and accessible TMB assessment panels and algorithms in more cancer types. 2020 Annals of Translational Medicine. All rights reserved.
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