Saturday, June 3, 2023
6/3/2023
PROJECT SUMMARY Environmental genotoxin exposure is responsible for 80-90% of the risk of developing cancer. Indeed, Whole Genome Sequencing studies show that human cancers carry mutational signatures reflective of the environmental agents to which the patients were exposed. However, some studies suggest that many mutational signatures arise from endogenous cellular processes. Mutations can arise when DNA is modified/damaged by exogenous physicochemical agents and endogenous cellular processes (e.g., oxidation). Agent-specific mutational signatures of environmental carcinogens reveal similarities to those found in human tumors. However, more common are the mutations related to endogenous processes known as ageing signatures i.e., SBS1 and SBS5. Understanding the origins of these signatures, which is key to a better understanding of cancer causes, requires a comprehensive approach to studying adducts. DNA adductomics aims to describe the totality of adducts in the genome, which are implicated in carcinogenesis. We hypothesize that exogenous agents act, at least in part, via the induction of signature patterns or types of adducts, but additionally they may also influence endogenous mutagenic processes, altering the DNA adductome. The aberrant alteration of endogenous processes would account for the low level of agent-specific mutations in tumors despite strong evidence for the key role of environmental agents in carcinogenesis. To begin to test this hypothesis, we will perform pilot studies to address the following aims: Aim 1, evaluate the impact of the endogenous DNA adductome upon the corresponding mutational landscape. In Aim 2, evaluate the impact of an exogenous environmental exposure (benzene) upon the endogenous DNA adductome, and corresponding mutational landscape. Analysis of the mutational landscapes, and their corresponding DNA adductome maps, will begin to advance our understanding of the relationships between the exposome, DNA adductome and mutatome, and hence enhance the results of the parent R01. Pursuing this route of investigation will pave the way for the identification/evaluation of cancer risk factors and the identification of novel mutational signatures caused by exogenous/endogenous exposures.
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