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	Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents
	Gao, Qiang ; Wang, Zhi-Chao ; Duan, Meng ; Lin, Yi-Hui ; Zhou, Xue-Ya ; Worthley, Daniel L. ; Wang, Xiao-Ying ; Niu, Gang ; Xia, Yuchao ; Deng, Minghua ; Liu, Long-Zi ; Shi, Jie-Yi ; Yang, Liu-Xiao ; Zhang, Shu ; Ding, Zhen-Bin ; Zhou, Jian ; Liang, Chun-Min ; Cao, Ya ; Xiong, Lei ; Xi, Ruibin ; Shi, Yong-Yong ; Fan, Jia
	2017
关键词	Liver Cancer Next-Generation Sequencing Patient-Derived Cell Lines Targeted Therapy INTRATUMOR HETEROGENEITY GENOMIC HETEROGENEITY TUMOR HETEROGENEITY DRUG-SENSITIVITY SEQUENCING DATA CANCER-CELLS LIVER-CANCER MUTATIONS EVOLUTION SORAFENIB
英文摘要	BACKGROUND & AIMS: No targeted therapies have been found to be effective against hepatocellular carcinoma (HCC), possibly due to the large degree of intratumor heterogeneity. We performed genetic analyses of different regions of HCCs to evaluate levels of intratumor heterogeneity and associate alterations with responses to different pharmacologic agents. METHODS: We obtained samples of HCCs (associated with hepatitis B virus infection) from 10 patients undergoing curative resection, before adjuvant therapy, at hospitals in China. We collected 4-9 spatially distinct samples from each tumor (55 regions total), performed histologic analyses, isolated cancer cells, and carried them low-passage culture. We performed whole-exome sequencing, copy-number analysis, and high-throughput screening of the cultured primary cancer cells. We tested responses of an additional 105 liver cancer cell lines to a fibroblast growth factor receptor (FGFR) 4 inhibitor. RESULTS: We identified a total of 3670 non-silent mutations (3192 missense, 94 splice-site variants, and 222 insertions or deletions) in the tumor samples. We observed considerable intratumor heterogeneity and branched evolution in all 10 tumors; the mean percentage of heterogeneous mutations in each tumor was 39.7% (range, 12.9%-68.5%). We found significant mutation shifts toward C>T and C>G substitutions in branches of phylogenetic trees among samples from each tumor (P <.0001). Of note, 14 of the 26 oncogenic alterations (53.8%) varied among subclones that mapped to different branches. Genetic alterations that can be targeted by existing pharmacologic agents (such as those in FGF19, DDR2, PDGFRA, and TOP1) were identified in intratumor subregions from 4 HCCs and were associated with sensitivity to these agents. However, cells from the remaining subregions, which did not have these alterations, were not sensitive to these drugs. High-throughput screening identified pharmacologic agents to which these cells were sensitive, however. Overexpression of FGF19 correlated with sensitivity of cells to an inhibitor of FGFR 4; this observation was validated in 105 liver cancer cell lines ( P = .0024). CONCLUSIONS: By analyzing genetic alterations in different tumor regions of 10 HCCs, we observed extensive intratumor heterogeneity. Our patient-derived cell line-based model, integrating genetic and pharmacologic data from multiregional cancer samples, provides a platform to elucidate how intratumor heterogeneity affects sensitivity to different therapeutic agents.; National Key Sci-Tech Project of China [2013ZX10002010]; National Natural Science Foundation of China [81522036, 81572292, 81372648, 81272725, 71532001]; National Program for Special Support of Eminent Professionals; Shanghai "Promising Youth Medical Worker" Project [13Y055]; National Key Basic Research Program of China [2015CB856000]; SCI(E); PubMed; ARTICLE; 1; 232-+; 152
语种	英语
出处	PubMed ; SCI
出版者	GASTROENTEROLOGY
内容类型	其他
源URL	[http://hdl.handle.net/20.500.11897/492865]
专题	数学科学学院
推荐引用方式 GB/T 7714	Gao, Qiang,Wang, Zhi-Chao,Duan, Meng,et al. Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents. 2017-01-01.

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