Abstract SY36-01: Somatic evolution, cancer, and our inevitable decline with age: Inextricably linked

Abstract

Abstract Why do we get cancer? Why is cancer highly associated with old age? Aging is associated with the accumulation of more mutations; some of which can contribute to cancer phenotypes. However, we now understand that carcinogenesis is much more complex than originally appreciated. In particular, there are tissue environmental forces that both impede and promote cancer evolution. Just as organismal evolution is known to be driven by environmental changes, cellular (somatic) evolution in our bodies is similarly driven by changes in tissue environments, whether caused by the normal process of aging, by lifestyle choices, or by extrinsic exposures. Environmental change promotes selection for new phenotypes that are adaptive to the new context. In our tissues, aging or insult-driven alterations in tissues drives selection for adaptive mutations, and some of these mutations can confer malignant phenotypes. To better understand the evolutionary forces that control somatic cell evolution, we used mouse models of cancer initiation, mathematical models of cellular evolution, and analyses of human tissue samples. We have shown that aging- and inflammation-dependent changes in stem cells and their tissue environments dramatically dictate whether cancer-causing mutations are advantageous to stem cells in our tissues, starting the cells down the path to cancer and deepening our insight into cancer risk. Recent studies from many labs have shown how as we age our tissues become dominated by clones bearing mutations in known cancer-associated genes. I will present studies from our labs exploring how cigarette smoking and aging can alter mutational landscapes in the non-malignant lung. To observe somatic mutations in lung biopsies from individuals with different smoking histories, we used a rare-mutation detection technique called Duplex Sequencing to analyze somatic variants from over 200 lung samples, including from subjects from the BDRE (Colorado), PEACE, and TRACERx cohorts. Using this method, we have identified large numbers of mutations in each brushing or biopsy, many of which are cataloged in the Catalogue Of Somatic Mutations In Cancer (COSMIC), and most of these are predicted to disrupt protein function. We also observe pervasive positive selection acting on mutations in many but not all of the cancer-associated genes, with different patterns of selection in the lungs of ever-smokers and never-smokers. Ongoing studies are using primary human and mouse lung epithelial cultures and mouse models to study how these mutations interact with smoking and age to alter associated clonal expansions, tissue integrity, and malignant progression. We propose a model whereby aging and microenvironmental changes induced through lifestyle choices like smoking can promote selection for cells with adaptive mutations, which can contribute to not only cancer risk but also tissue aging. Thus, while young tissues impede selection for such adaptive mutations, old age is associated with a feed-forward loop of aging tissue-mediated selection for mutant clones that then increase tissue aging. Thus, understanding the forces controlling clonal selection as we age and due to lifetime exposures could be critical for controlling multiple diseases of old age. [EJE, EL and FM contributed equally.These studies were led by CS and JD.] Citation Format: Edward J. Evans, Emilia Lim, Fabio Marongiu, Shi Biao Chia, William Hill, Clare Weeden, Oriol Pich, Andrew Rowan, Faiz Jabbar, Cristina Naceur-Lombardelli, Raju Veeriah, Moumita Ghosh, Daniel Merrick, York E. Miller, Robert Keith, Mariam Jamal-Hanjani, Charles Swanton, James V. DeGregori. Somatic evolution, cancer, and our inevitable decline with age: Inextricably linked [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY36-01.