Abstract IA009: Cancer is a disease of epigenetic stochasticity
Authors: Feinberg Andrew 
Published: May 2022

Abstract
My colleagues and I proposed in 2006 (1) that increased epigenetic stochasticity is a driving force of tumor progression from its origin to metastasis and would allow rapid selection for tumor cell survival at the expense of the host. More recently (2), we have been pursuing an idea that natural selection will favor the emergence of genetic loci for epigenetic variance, not just mean, for loci in which the environment changes unpredictably but often enough, and these epigenetically variable loci are critical to normal embryonic development and injury response. The idea is also relevant to cancer, in that increased epigenetic stochasticity would allow rapid selection for tumor cell survival at the expense of the host. This model puts epigenetic instability at the heart of tumor progression and is the primary target of cancer mutations. Several recent observations from the laboratory point to a genome-scale disruption of the epigenome that involves large blocks of variable DNA methylation and chromatin affecting shores and islands and increasing gene expression variability (3,4). We also find large-scale reprogramming of chromatin and DNA modifications during the natural evolution of distant metastasis, with dependence on the oxidative branch of the pentose phosphate pathway (5). We have also developed mathematically rigorous Gibbs-Boltzmann-style epigenetic landscapes incorporating stochasticity, and we have shown its relationship to entropy in information theory (6). Recent data show that this approach identifies epigenetic and genetic drivers of cancer, using acute lymphoblastic leukemia as a model (7). References: 1. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of human cancer. Nature Reviews Genetics 2006;7:21. 2. Feinberg AP, Irizarry RA. Stochastic epigenetic variation as a driving force of development, evolutionary adaptation, and disease. Proceedings of the National Academy of Sciences USA 2009;107 Suppl 1:1757-64. 3. Hansen KD et al. Increased variation in epigenetic domains across cancer types. Nature Genetics 2011;43:768-75. 4. Timp W, Feinberg AP. Cancer as a dysregulated epigenome allowing cellular growth advantage at the expense of the host. Nature Reviews Cancer 2013;13:497-510. 5. McDonald OG, et al. Large-scale epigenomic reprogramming links anabolic glucose metabolism to distant metastasis during the evolution of pancreatic cancer progression. Nature Genetics 2017;49:367-76. 6. Jenkinson G, Pujadas E, Goutsias J, Feinberg AP. Potential energy landscapes define the information-theoretic nature of the epigenome. Nature Genetics 2017;49:719-29. 7. Koldobskiy MA, et al. Informational content of methylomic landscapes reveals converging drivers of pediatric acute lymphoblastic leukemia. Koldobskiy MA et al. Nature Biomedical Engineering 2021;5:360-376.
Citation Format: Andrew Feinberg. Cancer is a disease of epigenetic stochasticity [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr IA009.