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Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens
Genes and Environment Laboratory, School of Public Health, University of California, Berkeley, CA 94720, USA
* Author to whom correspondence should be addressed.
Received: 18 May 2012; in revised form: 25 June 2012 / Accepted: 26 June 2012 / Published: 12 July 2012
Abstract: We have applied bioinformatic approaches to identify pathways common to chemical leukemogens and to determine whether leukemogens could be distinguished from non-leukemogenic carcinogens. From all known and probable carcinogens classified by IARC and NTP, we identified 35 carcinogens that were associated with leukemia risk in human studies and 16 non-leukemogenic carcinogens. Using data on gene/protein targets available in the Comparative Toxicogenomics Database (CTD) for 29 of the leukemogens and 11 of the non-leukemogenic carcinogens, we analyzed for enrichment of all 250 human biochemical pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The top pathways targeted by the leukemogens included metabolism of xenobiotics by cytochrome P450, glutathione metabolism, neurotrophin signaling pathway, apoptosis, MAPK signaling, Toll-like receptor signaling and various cancer pathways. The 29 leukemogens formed 18 distinct clusters comprising 1 to 3 chemicals that did not correlate with known mechanism of action or with structural similarity as determined by 2D Tanimoto coefficients in the PubChem database. Unsupervised clustering and one-class support vector machines, based on the pathway data, were unable to distinguish the 29 leukemogens from 11 non-leukemogenic known and probable IARC carcinogens. However, using two-class random forests to estimate leukemogen and non-leukemogen patterns, we estimated a 76% chance of distinguishing a random leukemogen/non-leukemogen pair from each other.
Keywords: leukemogen; pathway; Comparative Toxicogenomics Database; carcinogen; clustering
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Thomas, R.; Phuong, J.; McHale, C.M.; Zhang, L. Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens. Int. J. Environ. Res. Public Health 2012, 9, 2479-2503.
Thomas R, Phuong J, McHale CM, Zhang L. Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens. International Journal of Environmental Research and Public Health. 2012; 9(7):2479-2503.
Thomas, Reuben; Phuong, Jimmy; McHale, Cliona M.; Zhang, Luoping. 2012. "Using Bioinformatic Approaches to Identify Pathways Targeted by Human Leukemogens." Int. J. Environ. Res. Public Health 9, no. 7: 2479-2503.