Applying a Weight-of-Evidence Approach to Evaluate Relevance of Molecular Landscapes in the Exposure-Disease Paradigm.

Sherilyn A Gross,Kristen M Fedak

doi:10.1155/2015/515798

Abstract

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.

Highlights

In an idealistic view of carcinogenesis, the molecular initiation of a disease process can be directly tied to a genetic mutation or chromosome event caused by environmental exposure to a carcinogen
We asked the following: if exposure to a particular environmental carcinogen is implicated in the cause of a disease but the exposure is not evident at the time of disease diagnosis, what additional molecular events can be linked to the exposure-disease paradigm? Further, what additional mutational events can be linked to disease progression, as not every and not all exposures lead to disease outcomes? We propose that a “weight-of-evidence” (WoE) approach can be applied to compile evidence from multiple sources in the published literature to create a molecular landscape for the environmental carcinogen and for the disease endpoint in question
We suggest that common polymorphisms, genetic mutations, and epigenetic events be given the highest WoE ranking if the environmental carcinogen in question is directly or indirectly toxic through DNA adduct formation, and DNA repair mechanisms should be elevated, as genetic changes in DNA repair genes would be expected in the process of carcinogenesis in any tissue [2]

Summary

Introduction

In an idealistic view of carcinogenesis, the molecular initiation of a disease process can be directly tied to a genetic mutation or chromosome event caused by environmental exposure to a carcinogen. A single event is usually insufficient to induce cancer and other secondary events such as additional gene mutations and/or chromosome changes are usually required [1] These additional events occur during the latency period of the disease and the progression of the disease is a function of individual susceptibility and geneenvironment interactions [2]. While there are multiple types of mutations identified in cancers, it has been suggested that frank carcinogenesis occurs only when cells acquire defects in the following six key areas of cellular control [2]:. Molecular landscapes have been used to help establish the six key defects that are the hallmark of frank carcinogenesis; understanding the timing and order of occurrence of these molecular events during the latency period is ongoing

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Conclusion