New Short Term Prediction Method for Chemical Carcinogenicity by Hepatic Transcript Profiling following 28-Day Toxicity Tests in Rats

Abstract

We have previously shown the hepatic gene expression profiles of carcinogens in 28-day toxicity tests were clustered into three major groups (Group-1 to 3). Here, we developed a new prediction method for Group-1 carcinogens which consist mainly of genotoxic rat hepatocarcinogens. The prediction formula was generated by a support vector machine using 5 selected genes as the predictive genes and predictive score was introduced to judge carcinogenicity. It correctly predicted the carcinogenicity of all 17 Group-1 chemicals and 22 of 24 non-carcinogens regardless of genotoxicity. In the dose-response study, the prediction score was altered from negative to positive as the dose increased, indicating that the characteristic gene expression profile emerged over a range of carcinogen-specific doses. We conclude that the prediction formula can quantitatively predict the carcinogenicity of Group-1 carcinogens. The same method may be applied to other groups of carcinogens to build a total system for prediction of carcinogenicity.

CARCINOscreen®: New short-term prediction method for hepatocarcinogenicity of chemicals based on hepatic transcript profiling in rats

“…The carcinogenic substances contained in each group were previously reported in a study examining the gene expression patterns of carcinogens (Matsumoto et al, 2009(Matsumoto et al, , 2011. Table 1 summarizes the toxicity test conditions, carcinogenic properties, and carcinogen group number (Group-1 to 3) as determined in a previous study of the test chemicals (Matsumoto et al, 2009(Matsumoto et al, , 2011. The carcinogens group was determined based on the similarity of gene expression patterns.…”

“…Based on previous studies (Matsumoto et al, 2011), these genes were selected based on two criteria as follows: the first criterion was that the Welch t-value of the log 2 ratio between the training sets of carcinogens and non-carcinogens was more than 3, where the log 2 ratio is the logarithm to base 2 of the mean of the signal intensity ratio between the treated sample and the vehicle control. The Welch t-value is used for judging statistically whether the gene expression of carcinogens differs significantly, compared with non-carcinogens, as it is used in significance tests between two groups with possibly unequal variances.…”

“…We report here a novel prediction system, named "CARCINOscreen®," consisting of three prediction formulas generated from characteristic gene sets based on a previously reported method for establishing carcinogenicity prediction formulas (Matsumoto et al, 2011).…”

Simpler alternative to CARCINOscreen^® based on quantitative PCR (qPCR)

“…After applying the log2 ratio data of 15 predictive genes to CARCINOscreen ® , the largest value among the predictive scores obtained using the three prediction formulae was determined as the final predictive score. The details of the microarray experiments for CARCINOscreen ® are described in Matsumoto et al (2009Matsumoto et al ( , 2011Matsumoto et al ( and 2014.…”

“…This system consists of three prediction formulae generated from 15 characteristically predictive genes. The accuracy of this microarray-based CARCINOscreen ® for carcinogenicity prediction is reported as 94.1% for training chemical sets, therefore, this prediction system may be a promising tool for predicting hepatocarcinogenicity of chemicals in rats (Matsumoto et al, 2009(Matsumoto et al, , 2011(Matsumoto et al, and 2014. However, microarray analysis requires specialized equipment and skilled bioinformatics approaches for data analysis, limiting its versatility for the toxicological applications.…”