Abstract IA04: Mutational spectra of environmental carcinogens as biomarkers for early detection of cancer

Abstract In a multicellular organism, somatic mutations represent a permanent record of the biochemical perturbations experienced by a cell in its local microenvironment. Akin to a perpetual recording device, with every replication, genomic DNA accumulates mutations in patterns that reflect: i) the sequence context-dependent formation of DNA damage, due to environmental or endogenous reactive species, including spontaneous processes; ii) the activity of DNA repair pathways, which, depending on the type of lesion, can erase, ignore, or exacerbate the mutagenic consequences of that DNA damage; and iii) the choice of replication machinery that synthesizes the nascent genomic copy. These three factors result in a richly contoured sequence context-dependent mutational spectra, each characteristic of each type of DNA damage. Such mutagenic legacy, if appropriately decoded, can reveal the local history of genome-altering events such as chemical or pathogen exposures, metabolic stress, and inflammation, which in turn can provide an indication of the underlying causes and mechanisms of genetic disease. Modern tools have positioned us to develop a deep mechanistic understanding of the cellular factors and pathways that modulate a mutational process and, in turn, provide opportunities for better diagnostic and prognostic biomarkers, better exposure risk assessment, and even actionable therapeutic targets. One such tool is duplex consensus sequencing (DS), which is a type of highly accurate sequencing that allows the recording of mutational spectra of carcinogens from heterogenous collections of cells. Using DS, we identified the characteristic high-resolution mutational spectrum of the liver carcinogen aflatoxin B1 in a mouse model, 6-9 months before aflatoxin-induced tumors are detectable. In human terms, this timeline corresponds to the detection of a carcinogen exposure, through their mutational spectrum, 1-2 decades before clinical disease. Our DS spectrum is highly similar to the mutational spectra of aflatoxin recorded in cell culture, mouse tumors, and the computationally extracted mutational signature of aflatoxin (signature 24) from human tumors, suggesting that its features reflect fundamental sequence-context dependent biochemical processes of lesion formation, repair avoidance, and misreplication. Importantly, while the exposure to carcinogen, as quantified through its mutational imprint, increases the odds of cancer development, it does not provide direct information on the rate of tumor formation. Gender-specific differences and the presence of tumor-promoting factors are strong modulators of the rate of cancer development under the same carcinogen exposure conditions. Nevertheless, mutational spectra as biomarkers of carcinogen exposure present a significant clinical promise. The identification of at-risk individuals, based on their exposure mutational spectra, could lead to accelerated screening programs and early detection of malignancies at a surgically resectable stage. Citation Format: Bogdan I. Fedeles, Supawadee Chawanthayatham, Amanda L. Armijo, Robert G. Croy, John M Essigmann. Mutational spectra of environmental carcinogens as biomarkers for early detection of cancer [abstract]. In: Proceedings of the AACR Special Conference on Environmental Carcinogenesis: Potential Pathway to Cancer Prevention; 2019 Jun 22-24; Charlotte, NC. Philadelphia (PA): AACR; Can Prev Res 2020;13(7 Suppl): Abstract nr IA04.