Abstract 2198: The impact of carcinogens, obesity, and chronic inflammatory processes on mutational signatures and cancer risk in mouse tumor models
Authors: Li Yun Rose , Halliwill Kyle , Kandyba Eve , Delrosario Reyno , Tran Quan , Bayani Nora , Wu Di , Mirzoeva Olga , Reeves Melissa McCreery , Islam Mishu , Riva Laura , Bergstrom Eric , Digiovanni John , Alexandrov Ludmil , Balmain Allan 
Published: June 2022

Abstract
An estimated 40% of all human cancers are suspected to be a result of modifiable risk factors such as obesity, high fat diet and chronic inflammation. Whole genome sequencing (WGS) of thousands of human tumors have revealed “mutational signatures” that provide a molecular footprint of cancer origins. Whether such signatures exist for modifiable cancer risk factors remains unclear. We studied the impact of lifestyle risk factors using a compendium of 107 mouse tumors that model obesity, high fat diet, wounding, chronic inflammation, or chemotherapy. We used a well-established 2-step skin carcinogenesis model composed of exposure to mutagen DMBA followed by tumor promoter TPA, generating squamous carcinomas that were analysed by WGS for identification of mutational signatures. In addition to recapitulating many COSMIC human signatures, we identified a novel SNV signature induced by a single treatment with DMBA (SBS.DMBA) which explains the majority of all detected mutations. While a single exposure of normal skin to DMBA induces a highly variable number of carcinogen-specific mutations, a very high mutation burden is insufficient for tumorigenesis. SNVs attributable to reactive oxygen species (ROS) are broadly found in about 25% of all mouse tumors, but are most prominent in tumors from mice that are exposed to DMBA in utero, suggesting that the developmental age of mutagen exposure may impact the repair of ROS generated mutations and that the timing of exposure is a poorly understudied component of carcinogenesis. In mouse tumor models of genetic and dietary obesity, the total mutational load and mutational signatures in tumors from obese mice were indistinguishable from those of lean mice despite dramatic differences in tumor latency and progression as well transcriptomic differences in immune activation. We found an enrichment in deleterious Tgfrb2 mutations in tumors from mice with low compared to high body mass index (BMI) (p&lt;0.016). Using a conditionally activated RAS mouse model, we also show that a non-mutagenic inflammatory signal such as a chronic wound can act as the rate-limiting step for full tumor development. Surprisingly these tumors can be evoked even in somatic genomes with very few mutations apart from the initiating Ras driver. Finally, together with the Riva et al study, these chemically induced mouse tumors recapitulate &gt;50% of established human cancer driver genes. DMBA caused 91% of all Hras/Kras mutations, but only a minority of other recurrent driver mutations in genes such as Trp53 and Tert, suggesting that these occur later during the process of carcinogenesis. Taken together, we have analyzed the largest compendium of WGS data from nearly 300 mouse tumors, showing that while exogenous promotional factors do not increase mutation burden or induce novel mutational patterns, they have a major rate-limiting role in determining cancer risk.
Citation Format: Yun Rose Li, Kyle Halliwill, Eve Kandyba, Reyno Delrosario, Quan Tran, Nora Bayani, Di Wu, Olga Mirzoeva, Melissa McCreery Reeves, Mishu Islam, Laura Riva, Eric Bergstrom, John Digiovanni, Ludmil Alexandrov, Allan Balmain. The impact of carcinogens, obesity, and chronic inflammatory processes on mutational signatures and cancer risk in mouse tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2198.