已入深夜,您辛苦了!由于当前在线用户较少,发布求助请尽量完整地填写文献信息,科研通机器人24小时在线,伴您度过漫漫科研夜!祝你早点完成任务,早点休息,好梦!

Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents

六氯环己烷 肝细胞癌 癌症研究 生物 克拉斯 遗传异质性 PDGFRA公司 索拉非尼 突变 错义突变 靶向治疗 癌症 外显子组 外显子组测序 基因 遗传学 表型 主旨 间质细胞
作者
Qiang Gao,Zhichao Wang,Meng Duan,Yi-Hui Lin,Xueya Zhou,Daniel L. Worthley,Xiaoying Wang,Gang Niu,Yuchao Xia,Minghua Deng,Long-Zi Liu,Jie-Yi Shi,Liu-Xiao Yang,Shu Zhang,Zhen-Bin Ding,Jian Zhou,Chun-Min Liang,Ya Cao,Lei Xiong,Ruibin Xi
出处
期刊:Gastroenterology [Elsevier BV]
卷期号:152 (1): 232-242.e4 被引量:119
标识
DOI:10.1053/j.gastro.2016.09.008
摘要

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.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.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).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.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
开朗万天完成签到 ,获得积分10
1秒前
科研助手6应助冰雪痕采纳,获得10
2秒前
ShenQ发布了新的文献求助10
4秒前
奶糖爱果冻完成签到 ,获得积分10
5秒前
甜甜的紫菜完成签到 ,获得积分10
6秒前
li完成签到 ,获得积分10
11秒前
shu完成签到,获得积分10
17秒前
Cathy完成签到,获得积分10
20秒前
JiayinLiu发布了新的文献求助50
22秒前
天天快乐应助认真的三问采纳,获得10
22秒前
狐狸小姐完成签到 ,获得积分10
22秒前
fane完成签到,获得积分10
23秒前
TY完成签到 ,获得积分10
24秒前
ShenQ完成签到,获得积分10
25秒前
独立江湖女完成签到 ,获得积分10
25秒前
ling361发布了新的文献求助10
27秒前
七面东风完成签到,获得积分10
27秒前
OeO完成签到 ,获得积分10
27秒前
我是125完成签到,获得积分10
29秒前
小孟吖完成签到 ,获得积分10
30秒前
八二力完成签到 ,获得积分10
31秒前
grace完成签到 ,获得积分10
34秒前
田様应助雪生在无人荒野采纳,获得10
37秒前
彭于晏完成签到,获得积分10
37秒前
38秒前
ling361完成签到,获得积分10
39秒前
hairgod完成签到,获得积分10
40秒前
40秒前
沙与沫完成签到 ,获得积分10
40秒前
44秒前
44秒前
minuxSCI完成签到,获得积分10
44秒前
明时完成签到,获得积分10
48秒前
50秒前
50秒前
笨笨的寄真完成签到 ,获得积分10
51秒前
Becky完成签到 ,获得积分10
51秒前
54秒前
零知识完成签到 ,获得积分10
54秒前
伽拉发布了新的文献求助10
1分钟前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
Aktuelle Entwicklungen in der linguistischen Forschung 300
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3989957
求助须知:如何正确求助?哪些是违规求助? 3532034
关于积分的说明 11256000
捐赠科研通 3270880
什么是DOI,文献DOI怎么找? 1805070
邀请新用户注册赠送积分活动 882252
科研通“疑难数据库(出版商)”最低求助积分说明 809216