Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm.
Information on polymorphisms, mutations, and epigenetic events has become increasingly important in our understanding of molecular mechanisms associated with exposures-disease outcomes. Molecular landscapes can be developed to illustrate the molecular characteristics for environmental carcinogens as well as associated disease outcomes, although comparison of these molecular landscapes can often be difficult to navigate. We developed a method to organize these molecular data that uses a weight-of-evidence approach to rank overlapping molecular events by relative importance for susceptibility to an exposure-disease paradigm. To illustrate the usefulness of this approach, we discuss the example of benzene as an environmental carcinogen and myelodysplastic syndrome (MDS) as a causative disease endpoint. Using this weight-of-evidence method, we found overlapping polymorphisms in the genes for the metabolic enzymes GST and NQO1, both of which may infer risk of benzene-induced MDS. Polymorphisms in the tumor suppressor gene, TP53, and the inflammatory cytokine gene, TNF-α, were also noted, albeit inferring opposing outcomes. The alleles identified in the DNA repair gene RAD51 indicated an increased risk for MDS in MDS patients and low blood cell counts in benzene-exposed workers. We propose the weight-of-evidence approach as a tool to assist in organizing the sea of emerging molecular data in exposure-disease paradigms.
Cardno ChemRisk, 4840 Pearl East Circle 300 W., Boulder, CO 80304, USA.
Sherilyn A
SA
Gross
Department of Environmental & Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523, USA.
Kristen M
KM
Fedak
D001554:Benzene / Q000633:toxicity*; D001772:Blood Cell Count; D002274:Carcinogens, Environmental / Q000633:toxicity*; D004260:DNA Repair / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D016273:Occupational Exposure; D027361:Organic Anion Transporters / Q000235:genetics; D011110:Polymorphism, Genetic; D051135:Rad51 Recombinase / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D001554:Benzene; D002274:Carcinogens, Environmental; D016660:NAD(P)H Dehydrogenase (Quinone); D027361:Organic Anion Transporters; D051135:Rad51 Recombinase; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; C495901:TP53 protein, human; C487009:SLCO6A1 protein, human; C447479:NQO1 protein, human