Abstract 2739: Genetic characterization of an extensive panel of patient-derived xenograft tumor models of hepatocellular carcinoma for preclinical development.
Authors: Fang Douglas D. , Xu Qiang , Tan Yexiong , Chen Lei , Sun Hongye , Gu Qingyang , Zhang Bin , Luo Qin , Chen Shu-hui , Wang Hongyang , Chan Chi-Chung 
Published: August 2014

Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths. Half of the total HCC-related deaths and new cases occurred in China. Different from many cancers, HCC is intrinsically resistant to conventional chemotherapies, and many attempts to develop new systemic agents for HCC have failed in clinic. Lack of clinically relevant and genetically well-defined preclinical models critically accounts for the failures. In this study, we established an extensive panel of Chinese HCC patient-derived xenograft (PDX) models by directly transplanting surgically resected patient tumor tissues in BALB/c nude or SCID mice. Implantation of 254 patient samples resulted in 70 transplantable PDX models (27.6%) covering stage I, II, III, and IV tumors. Xenograft tissues could be serially passaged, cryopreserved, and revived with a success rate of over 94%. Early passages between p2-p4 of PDX tissues were used in the histological and molecular characterization. The histology of PDX tissues recapitulated the features of the original samples and maintained the heterogeneity of human tumors. Unsupervised hierarchical cluster analysis of gene expression profiles in 7 paired samples assessed by GeneChip® PrimeView™ Human Gene Expression Array revealed that PDX tumor tissues retained the global gene-expression patterns of patient samples. Using next-generation sequencing we performed exome sequencing of 43 of PDX models. Contaminated murine DNA reads were removed by a proprietary algorithm to eliminate homology bias. A wide variety of SNPs were identified and some may represent driver mutations, such as ones on JAK1 and JAK2 genes. Copy number variation analysis by Genome-Wide Human SNP Array 6.0 in 24 PDX models elucidated amplifications of a number of genes, including MET, AKT2, AKT3, mTOR, ALDH1A1, ALDH1A2, JUN and NOV. In vivo efficacy studies exhibited differential responses to standard-of-care compounds in the models. Collectively, with the current intense interest in development of targeted therapies, the use of patient liver cancer tissue-derived models with well genomic characterization provides an excellent, and perhaps more relevant, platform for preclinical studies of experimental therapeutics, and for biomarker discovery and translational research.
Citation Format: Douglas D. Fang, Qiang Xu, Yexiong Tan, Lei Chen, Hongye Sun, Qingyang Gu, Bin Zhang, Qin Luo, Shu-hui Chen, Hongyang Wang, Chi-Chung Chan. Genetic characterization of an extensive panel of patient-derived xenograft tumor models of hepatocellular carcinoma for preclinical development. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2739. doi:10.1158/1538-7445.AM2013-2739