title: Genomic characterization of a large panel of patient-derived hepatocellular carcinoma xenograft tumor models for preclinical development.
abstract: Lack of clinically relevant tumor models dramatically hampers development of effective therapies for hepatocellular carcinoma (HCC). Establishment of patient-derived xenograft (PDX) models that faithfully recapitulate the genetic and phenotypic features of HCC becomes important. In this study, we first established a cohort of 65 stable PDX models of HCC from corresponding Chinese patients. Then we showed that the histology and gene expression patterns of PDX models were highly consistent between xenografts and case-matched original tumors. Genetic alterations, including mutations and DNA copy number alterations (CNAs), of the xenografts correlated well with the published data of HCC patient specimens. Furthermore, differential responses to sorafenib, the standard-of-care agent, in randomly chosen xenografts were unveiled. Finally, in the models expressing high levels of FGFR1 gene according to the genomic data, FGFR1 inhibitor lenvatinib showed greater efficacy than sorafenib. Taken together, our data indicate that PDX models resemble histopathological and genomic characteristics of clinical HCC tumors, as well as recapitulate the differential responses of HCC patients to the standard-of-care treatment. Overall, this large collection of PDX models becomes a clinically relevant platform for drug screening, biomarker discovery and translational research in preclinical setting.
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Qingyang
authors.initials: Q
authors.lastname: Gu
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Hongye
authors.initials: H
authors.lastname: Sun
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China.
authors.forename: Yexiong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Guan
authors.initials: G
authors.lastname: Wang
authors.affiliation: Genome Center, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Weiguo
authors.initials: W
authors.lastname: Xu
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Shuqun
authors.initials: S
authors.lastname: Yang
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China.
authors.forename: Jing
authors.initials: J
authors.lastname: Fu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China.
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China.
authors.forename: Shengxian
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Guibai
authors.initials: G
authors.lastname: Liang
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Qunsheng
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Chen
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.
authors.forename: Chi-Chung
authors.initials: CC
authors.lastname: Chan
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Eastern Hepatobiliary Surgery Hospital/Institute of Shanghai, Shanghai, 200131 China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: Discovery Services, WuXi AppTec Co., Ltd., Waigaoqiao Free Trade Zone, Shanghai, 200131 China.|Current address: Cancer Translational Research and In Vivo Pharmacology, China Novartis Institute for Biomedical Research, Zhangjiang Hi-Tech Park, Pudong, Shanghai, 200131 China.
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Fang
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D023281:Genomics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017468:Receptors, Fibroblast Growth Factor
keywords: copy number alterations (CNA); fibroblast growth factor receptor (FGFR); hepatocellular carcinoma (HCC); patient-derived xenograft (PDX) tumor model; single nucleotide polymorphism (SNP)