Abstract NG01: Accumulation of somatic mutations in normal and cancerous tissues with age

Abstract

Abstract Fundamental theories in carcinogenesis and aging evoke the accumulation of rare somatic mutations in normal tissues over time. However, absence of a simple and systematic method to characterize somatic mutations in normal tissues precludes the understanding of their functional consequences. We present Bottleneck Sequencing System (BotSeqS), a next-generation sequencing method that quantitates rare somatic point mutations simultaneously across the mitochondrial and nuclear genomes. BotSeqS combines molecular barcoding with a simple dilution step immediately before library amplification. Using BotSeqS, we determine the mutation frequencies and spectra in normal brain, kidney, and colon from a total of 34 individuals ranging from < 1 to 98 years old. We show an age and tissue-dependent accumulation of rare point mutations and demonstrate that the somatic mutational burden in normal tissues can vary by several orders of magnitude depending on biological and environmental factors. For example, individuals with defects in the mismatch repair machinery or exposure to environmental carcinogens (smoking, aristolochic acid) show significant increases in mutational frequencies and altered mutational spectra compared to controls. We further show major differences between the mutational patterns of the mitochondrial and nuclear genomes in normal tissues. Lastly, we find that the mutational spectra of normal tissues were different from each other but similar to cancers from the same tissue type, suggesting that the differential mutational spectra observed in cancers are tissue-specific rather than cancer-specific. This technology can provide insights into the number and nature of genetic alterations in normal tissues and can be used to address a variety of fundamental questions about the genomes of diseased tissues. Citation Format: Margaret L. Hoang, Isaac Kinde, Cristian Tomasetti, Thomas Rosenquist, Arthur P. Grollman, Kenneth W. Kinzler, Bert Vogelstein, Nickolas Papadopoulos. Accumulation of somatic mutations in normal and cancerous tissues with age. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr NG01.