Global S&T Development Trend Analysis Platform of Resources and Environment
DOI | 10.1289/EHP3986 |
The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity | |
Li, Amy1,2,6; Lu, Xiaodong3; Natoli, Ted3; Bittker, Joshua3; Sipes, Nisha S.4; Subramanian, Aravind3; Auerbach, Scott4; Sherr, David H.5; Monti, Stefano1,2,6 | |
2019-04-01 | |
发表期刊 | ENVIRONMENTAL HEALTH PERSPECTIVES
![]() |
ISSN | 0091-6765 |
EISSN | 1552-9924 |
出版年 | 2019 |
卷号 | 127期号:4 |
文章类型 | Article |
语种 | 英语 |
国家 | USA |
英文摘要 | BACKGROUND: Most chemicals in commerce have not been evaluated for their carcinogenic potential. The de facto gold-standard approach to carcinogen testing adopts the 2-y rodent bioassay, a time-consuming and costly procedure. High-throughput in vitro assays arc a promising alternative for addressing the limitations in carcinogen screening. OBJECTIVES: We developed a screening process for predicting chemical carcinogenicity and genotoxicity and characterizing modes of actions (MoAs) using in vitro gene expression assays. METHODS: We generated a large toxicogenomics resource comprising similar to 6,000 expression profiles corresponding to 330 chemicals profiled in HepG2 (human hepatocellular carcinoma cell line) at multiple doses and replicates. Predictive models of carcinogenicity and genotoxicity were built using a random forest classifier. Differential pathway enrichment analysis was performed to identify pathways associated with carcinogen exposure. Signatures of carcinogenicity and genotoxicity were compared with external sources, including Drugmatrix and the Connectivity Map. RESULTS: Among profiles with sufficient bioactivity, our classifiers achieved 72.2% Area Under the ROC Curve (AUC) for predicting carcinogenicity and 82.3% AUC for predicting genotoxicity. Chemical bioactivity, as measured by the strength and reproducibility of the transcriptional response, was not significantly associated with long-term carcinogenicity in doses up to 40 mu M. However, sufficient bioactivity was necessary for a chemical to be used for prediction of carcinogenicity. Pathway enrichment analysis revealed pathways consistent with known pathways that drive cancer, including DNA damage and repair. The data is available at https://cluelo/CRCON ABC, and a portal for query and visualization of the results is accessible at haps://carcinogenome.org. DISCUSSION: We demonstrated an in vitro screening approach using gene expression profiling to predict carcinogenicity and infer MoAs of chemical perturbations. |
领域 | 资源环境 |
收录类别 | SCI-E |
WOS记录号 | WOS:000467131100007 |
WOS关键词 | NATIONAL-TOXICOLOGY-PROGRAM ; INDOXYL SULFATE ; CANCER ; TOXICITY ; TOXICOGENOMICS ; DATABASE ; HAZARD ; MECHANISMS ; SIGNATURES ; DISCOVERY |
WOS类目 | Environmental Sciences ; Public, Environmental & Occupational Health ; Toxicology |
WOS研究方向 | Environmental Sciences & Ecology ; Public, Environmental & Occupational Health ; Toxicology |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://119.78.100.173/C666/handle/2XK7JSWQ/182023 |
专题 | 资源环境科学 |
作者单位 | 1.Boston Univ, Sch Med, Computat Biomed, Boston, MA 02118 USA; 2.Boston Univ, Bioinformat Program, Boston, MA 02215 USA; 3.Broad Inst MIT & Harvard, Canc Program, Cambridge, MA 02142 USA; 4.NIEHS, Toxicoinformat Grp, Durham, NC USA; 5.Boston Univ, Sch Publ Hlth, Dept Environm Hlth, Boston, MA USA; 6.72 East Concord St E611, Boston, MA 02118 USA |
推荐引用方式 GB/T 7714 | Li, Amy,Lu, Xiaodong,Natoli, Ted,et al. The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity[J]. ENVIRONMENTAL HEALTH PERSPECTIVES,2019,127(4). |
APA | Li, Amy.,Lu, Xiaodong.,Natoli, Ted.,Bittker, Joshua.,Sipes, Nisha S..,...&Monti, Stefano.(2019).The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity.ENVIRONMENTAL HEALTH PERSPECTIVES,127(4). |
MLA | Li, Amy,et al."The Carcinogenome Project: In Vitro Gene Expression Profiling of Chemical Perturbations to Predict Long-Term Carcinogenicity".ENVIRONMENTAL HEALTH PERSPECTIVES 127.4(2019). |
条目包含的文件 | 条目无相关文件。 |
除非特别说明,本系统中所有内容都受版权保护,并保留所有权利。
修改评论