Abstract LB-226: Integrative pharmacogenomic analysis of patient-derived xenografts of Chinese hepatocellular carcinoma
Authors: Zhou Hui , Lu Haisong , Shi Yujian , Hu Gang , Zhou He , Yang Xueyan , Ouyang Limei , Zhu Xiaolong , Gong Zhuolin , Tao Weikang 
Published: May 2015

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths. Patient derived xenografts (PDX), generated by direct engraftment of tumor samples from the patients into immunocompromised mice can be used as an in vivo platform that provides the opportunity to test proposed personalized medicine strategies. In this study, comprehensive molecular characterizations of 28 Chinese HCC PDX models were done by both whole genome sequencing (WGS) and RNAseq technology. After removing contaminated murine DNA/RNA reads by a proprietary algorithm (unpublished) to eliminate homology bias, more than 35 million reads per sample were analyzed in the RNAseq experiment, and at least average 40X coverage at each base of DNA in the WGS experiment. In order to find meaningful targets with high confidence, we integrated multiple lines of evidences from both DNA and RNA levels. Out of 346 gene fusion events were identified in 28 HCC PDXs, 51 occurred in more than one sample and 13 were supported by structural variation evidence from WGS dataset.

The same passages (between p3-p5) of 24 PDX tissues were also treated with Sorafenib in the efficacy studies and showed differential responses. The expression of 482 genes (2%) is statistically significantly correlated with drug sensitivity (p-value &lt;0.05), 198 of them (41%) are positively correlated. In the single nucleotide variation (SNV) and indel analysis of WGS dataset, 162 genes were identified as highly mutated genes (p-value &lt;0.05), including classical cancer driver gene TP53. Total 27401 novel SNVs in these 162 genes were identified, 991 (3.6%) of them are nonsynonymous. 557 (2%) SNVs are statistically significantly correlated with drug sensitivity status (p-value&lt;0.05), 28 are nonsynonymous. Pathway analysis shows that these drug responses related genes are enriched in focal adhension formation, induction of apoptosis, P53 signaling pathway, DNA damage response and cell cycle checkpoint.

Comparing to other similar studies, our approach of integrative analysis of WGS (vs. Whole exome sequencing) and RNAseq (vs. microarray) provided the most comprehensive genetic insights/landscapes of HCC patients and genetic alterations’ relationship to the drug responses. It also demonstrated that PDX models provide rich information for preclinical studies of experimental therapeutics, and an excellent resource for biomarker discovery and translational research.

Citation Format: Hui Zhou, Haisong Lu, Yujian Shi, Gang Hu, He Zhou, Xueyan Yang, Limei Ouyang, Xiaolong Zhu, Zhuolin Gong, Weikang Tao. Integrative pharmacogenomic analysis of patient-derived xenografts of Chinese hepatocellular carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-226. doi:10.1158/1538-7445.AM2014-LB-226