A Pharmacogenomic Landscape in Human Liver Cancers

Zhixin Qiu; Hong Li; Zhengtao Zhang; Zhenfeng Zhu; Sheng He; Xujun Wang; Pengcheng Wang; Jianjie Qin; Liping Zhuang; Wei Wang; Fubo Xie; Ying Gu; Keke Zou; Chao Li; Chun Li; Chenhua Wang; Jin Cen; Xiaotao Chen; Yajing Shu; Zhao Zhang; Lulu Sun; Lihua Min; Yong Fu; Xiaowu Huang; Hui Lv; He Zhou; Yuan Ji; Zhigang Zhang; Zhiqiang Meng; Xiaolei Shi; Haibin Zhang; Yixue Li; Lijian Hui

doi:10.1016/j.ccell.2019.07.001

A Pharmacogenomic Landscape in Human Liver Cancers

Cancer Cell. 2019 Aug 12;36(2):179-193.e11. doi: 10.1016/j.ccell.2019.07.001. Epub 2019 Aug 1.

Authors

Zhixin Qiu¹, Hong Li², Zhengtao Zhang¹, Zhenfeng Zhu³, Sheng He⁴, Xujun Wang⁵, Pengcheng Wang⁶, Jianjie Qin⁷, Liping Zhuang³, Wei Wang⁸, Fubo Xie⁸, Ying Gu⁸, Keke Zou², Chao Li², Chun Li¹, Chenhua Wang¹, Jin Cen¹, Xiaotao Chen¹, Yajing Shu¹, Zhao Zhang¹, Lulu Sun¹, Lihua Min¹, Yong Fu⁹, Xiaowu Huang⁶, Hui Lv⁵, He Zhou⁸, Yuan Ji¹⁰, Zhigang Zhang¹¹, Zhiqiang Meng³, Xiaolei Shi¹², Haibin Zhang¹³, Yixue Li¹⁴, Lijian Hui¹⁵

Affiliations

¹ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
² CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
³ Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁴ CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China.
⁵ SJTU-Yale Joint Center for Biostatistics, Department of Bioinformatics and Biostatistics, Shanghai Jiaotong University, Shanghai 200240, China.
⁶ Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China.
⁷ Liver Transplantation Center, Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
⁸ Shanghai ChemPartner Co., Ltd., Shanghai 201203, China.
⁹ Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
¹⁰ Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
¹¹ Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
¹² Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 211166, China. Electronic address: njsxl2000@163.com.
¹³ Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China. Electronic address: drzhanghb@163.com.
¹⁴ CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: yxli@sibs.ac.cn.
¹⁵ State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China; Bio-Research Innovation Center Suzhou, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou, Jiangsu 215121, China. Electronic address: ljhui@sibcb.ac.cn.

Abstract

Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.

Keywords: liver cancer; patient-derived cancer models; pharmacogenomics; sorafenib.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antineoplastic Agents / pharmacology*
Asian People / genetics
Biomarkers, Tumor / genetics*
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / ethnology
Carcinoma, Hepatocellular / genetics*
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Clinical Decision-Making
Databases, Genetic
Drug Resistance, Neoplasm / genetics
Female
Genetic Heterogeneity
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
Humans
Liver Neoplasms / drug therapy*
Liver Neoplasms / ethnology
Liver Neoplasms / genetics*
Liver Neoplasms / pathology
Male
Mice, Inbred BALB C
Mice, Inbred NOD
Mice, Nude
Mice, SCID
Patient Selection
Pharmacogenomic Testing
Pharmacogenomic Variants*
Phenotype
Precision Medicine
Protein Kinase Inhibitors / pharmacology*
Sorafenib / pharmacology*
Xenograft Model Antitumor Assays

Substances

Antineoplastic Agents
Biomarkers, Tumor
Protein Kinase Inhibitors
Sorafenib

Grants and funding

P30 CA008748/CA/NCI NIH HHS/United States