Abstract
Mouse models of cancer have been instrumental in the development of our understanding of the processes that drive multistage carcinogenesis from the initiation stage to metastasis. Tumors induced in mice by exposure to carcinogenic chemicals replicate many of the biologic and genetic features of multistage cancer in human populations. Skin and lung tumors initiated by chemical mutagens generally have carcinogen-specific mutations in Hras and Kras, respectively. However, these mutation patterns are seen not only in the target Ras genes, but also can be detected genome-wide as “mutational signatures” that are diagnostic for each carcinogen. We have extended this concept to search for new mutation signatures in tumors induced in mice by a wide range of physical (high- and low-energy radiation) and chemical carcinogens to which humans are exposed. In collaboration with the National Toxicology Program and the Sanger Institute (UK), we have carried out whole-genome and/or -exome sequencing of several hundred mouse tumors induced by a wide range of known or suspected human carcinogens. Our data identify highly variable tumor genomic imprints of carcinogen exposure as reflected in the relative numbers and types of structural variants (copy number changes, translocations, complex rearrangements) and point mutational signatures found in tumors induced by different agents. Analysis of these mutation patterns may illuminate the specific mechanisms by which these agents act to initiate or promote cancer development and provide novel information for use in risk assessment.
Citation Format: Allan Balmain. Mutational signatures of environmental carcinogens in mouse and human cancers [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 IA06.
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