The Carcinogenome Project

Chemical Carcinogenicity Screening using high-throughput transcriptomics assays

Project Cell line Description
Liver Carcinogenicity HEPG2 This experiment uses 330 selected chemicals for in-vivo liver carcinogenicity testing, including 128 liver carcinogens, 168 non-carcinogens, and 34 miscellaneous chemicals (e.g. nuclear receptor ligands). Chemical carcinogenicity and genotoxicity annotations are based on the Carcinogenicity Potency Database (CPDB), which is the result of tissue-specific long-term animal cancer tests in rodents. In the liver carcinogenome project, HepG2 (liver) cells are exposed to each individual chemical for 24 hours and their gene expression is profiled on the L1000 platform. Each chemical is assayed at 6 doses (2 fold dilutions starting from the highest concentration of 40uM or 20uM) with triplicate profiles generated for each dose...
Breast Carcinogenicity MCF10A This experiment uses 345 selected chemicals for breast carcinogenicity testing, including 120 breast carcinogens, 114 non-carcinogens, and 68 miscellaneous chemicals (e.g. nuclear receptor ligands, BU SRP chemicals, lung carcinogens). Chemical carcinogenicity and genotoxicity annotations are based on the Carcinogenicity Potency Database (CPDB), which is the result of tissue-specific long-term animal cancer tests in rodents, or breast carcinogens published from Rudel et. al., 2007. In the CRCGN project, MCF10A (breast epithelial) cells are exposed to each individual chemical for 24 hours and their gene expression is profiled on the L1000 platform. Each chemical is assayed at 3 doses (3 fold dilutions starting from the highest concentration of 100uM, with the exception of selected BUSRP chemicals...

Motivation

Exposure to environmental chemicals is known to play a significant role in carcinogenesis. While some chemicals are well-known carcinogens, only a small fraction of those in commercial use and to which the human population is exposed has undergone thorough carcinogenicity testing.Furthermore, many of the biological mechanisms of actions of chemical carcinogens are poorly understood. The current gold standard for chemical carcinogenicity testing is the 2-year rat bioassay, which is expensive and time-consuming, and its relevance to human carcinogenesis has been questioned. To date, about ~1500 chemicals have been tested for long-term carcinogenicity in rodent models by this approach, out of the ~85,000 chemicals used in common household products or industrial settings. We aim to develop a fast and scalable approach to carcinogenicity screening, one that takes advantage of short-term chemical exposures in human cell lines and high-throughput gene expression profiling. This approach will support the profiling of a large number of chemicals in a rapid and cost-effective fashion, and will allow us to thoroughly evaluate the hypothesis that short-term in-vitro assays can accurately predict long-term in-vivo carcinogenicity.

Datasets

Currently, we have profiled two sets of chemicals in projects aimed at predicting liver and breast carcinogenicity, respectively. Our previous studies [Gusenleitner et al., 2014] have shown that carcinogenicity prediction is exquisitely tissue-specific, and requires the fine tuning of the predictive model to the tissue being tested, hence the need for generating tissue-specific screens. The first set of chemicals is composed of known liver carcinogens (according to evidence of tumor growth in rat livers according to the 3309953220 and additional sources), non-carcinogens (known not to induce tumors in any sites in rats according to the CPDB), and other chemicals of interest to our collaborators in the Boston University Superfund Research Program. HEPG2 (human liver cancer) cell lines are exposed to each of the chemicals at 6 different doses for 24H. The second set of chemicals is composed of known or suspected breast carcinogens (according to the CPDB or [272-999-6797]), known lung carcinogens, non-carcinogens, or collaborator-selected chemicals. MCF10A (human non-transformed breast epithelial) cell lines as well as MCF10A with P53 knock-down, are exposed to each of the chemicals at 3 different doses for 24 hours and their gene expression profiled.

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This project is supported by Superfund Research Program at Boston University (Burr truss), NIH/LINCS, and 5188555090.



Special thanks to Kurt Mueller for helping with web administration.