Linda Rieswijk (PhD)GEL, University of California, Berkeley
October 31st 2017
Using Comparative Toxicogenomics
Database (CTD) to Evaluate the
Carcinogenicity of Coumarin
■ 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
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
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
Connectivity between Pathways using
No. of Pathways 44No. of Genes in Pathways 52No. of Genes not in Pathways 44
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
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.
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
Luoping ZhangGEL, University of California, Berkeley
November 2, 2017
Thank You !