using comparative toxicogenomics database (ctd) to ... · pdf file robust, publicly available...
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Linda Rieswijk (PhD)GEL, University of California, Berkeley
October 31st 2017
Using Comparative Toxicogenomics
Database (CTD) to Evaluate the
Carcinogenicity of Coumarin
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■ http://ctdbase.org
■ Robust, publicly available database aims to advance understandingabout how environmental exposures affect human health.
■ Release of October 2017 contains:
Chemical–gene interactions (curated) 1,621,428
Unique chemicals 12,524
Unique genes 43,714
Unique organisms 572
Gene–disease associations 21,429,161
Curated[1] 35,539
Unique genes 7,895
Unique diseases 5,526
Inferred[2] 21,393,622
Unique genes 42,727
Unique diseases 3,111
Chemical–disease associations 2,336,715
Curated[1] 208,049
Unique chemicals 9,348
Unique diseases 3,158
Inferred[2] 2,128,666
Unique chemicals 12,271
Unique diseases 5,514
1 Davis AP et al., The Comparative Toxicogenomics Database: update 2017. Nucleic Acids Res. 2016 Sep 19 [Epub ahead of print]
Comparative Toxicogenomics Database1
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Workflow
■ All genes associated with chemical X (Coumarin)
■ All genes associated with disease Y (Cancer)
■ Find genes overlapped between X and Y
■ Visualize molecular/gene interaction networks
■ Look for large clusters of genes in a functionally
grouped network
■ Identify pathways in which the chemical-induced
disease genes are involved (enrichment analysis)
■ Biological pathways (~1500) can be linked with
the key characteristics of humans carcinogens
Goal: Identify Genes, Pathways & KC
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Studies & Genes: Coumarin (COU) & Neoplasms (NEO)
43% (96/222) of COU_Genes overlapped with NEO_Genes
The term “neoplasms” includes curated* genes associated with cancers
of liver, lung, kidney, forestomach, pancreatic and many other types.
* Curated genes are:
1) Genes that may be a biomarker of a disease (e.g., increased expression of gene X correlates with disease Y) or play a role
in the etiology of a disease (e.g., mutations in gene X causes disease Y); or
2) A gene that is or may be a therapeutic target in the treatment of a disease (e.g., targeted reduction of gene X expression
reduces susceptibility to disease Y).
222 3152
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Connectivity between Pathways using
No. of Pathways 44No. of Genes in Pathways 52No. of Genes not in Pathways 44
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Affected Top 20 WikiPathways Obtained Using ClueGO(min 3 genes or 4% of total, kappa-score 0.4 and p-val<0.05)
Ten Key Characteristic Pathway Name
# of Associated
genes found
# of All associated
genes
% Associated
genesTerm
P-value
5Photodynamic therapy-induced NFE2L2 (NRF2) survival
signaling 7 24 29.17 1.271E-085 NRF2 pathway 13 146 8.90 2.925E-085 Selenium Micronutrient Network 9 89 10.11 1.637E-060 Folate Metabolism 8 67 11.94 1.813E-065 Oxidative Stress 6 31 19.35 2.109E-065 Amyotrophic lateral sclerosis (ALS) 6 38 15.79 7.364E-06
0Photodynamic therapy-induced unfolded protein
response 5 27 18.52 1.993E-058 Aryl Hydrocarbon Receptor Pathway 6 46 13.04 2.303E-055 Photodynamic therapy-induced AP-1 survival signaling 6 50 12.00 3.752E-050 Vitamin B12 Metabolism 6 52 11.54 4.710E-051 Estrogen metabolism 4 18 22.22 6.748E-051 Aflatoxin B1 metabolism 3 7 42.86 6.904E-05
11 Overview of nanoparticle effects 4 19 21.05 8.464E-051 Tamoxifen metabolism 4 21 19.05 1.282E-040 Amino Acid metabolism 7 91 7.69 1.496E-048 Aryl Hydrocarbon Receptor 5 46 10.87 2.798E-041 Metapathway biotransformation 9 179 5.03 4.326E-040 One carbon metabolism and related pathways 5 52 9.62 4.997E-041 Valproic acid pathway 3 13 23.08 5.336E-040 Trans-sulfuration and one carbon metabolism 4 31 12.90 6.114E-04
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Key Characteristics of Coumarin-Associated Pathways (n=44 from 52 involved genes)
Ten Key Characteristics # Associated Pathways
1. Metabolic activation 8
2. Genotoxicity 0
3. Altered DNA repair 1
4. Epigenetic alterations 0
5. Oxidative stress 10
6. Chronic inflammation 3
7. Immunosuppression 0
8. Modulation of receptor 3
9. Immortalization 0
10. Altered cell proliferation 3
Not Applicable (0) 14
Multiple characteristics (11) 2
Oxidative Stress
More oxidative stress (KC5) and metabolic activation (KC1) pathways are affected;
Five key characteristics are involved in the potential carcinogenicity of coumarin.
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Summary of Coumarin-involvedGenes, Pathways & Key Characteristics
Summary # Genes/Pathways/KCs
CTD: Coumarin Genes 222
CTD: Neoplasm Genes 3152
CTD: Overlap COU-Genes and NEO-Genes 96
ClueGO: # of Genes not present in Pathways 44
ClueGO: # of Genes present in Pathways 52
ClueGO: Number of Pathways 44
wikiPathway: # of Key Characteristics involved 5 of 10
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Luoping ZhangGEL, University of California, Berkeley
November 2, 2017
Thank You !