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Environ Mol Mutagen. 2019 Oct 8. doi: 10.1002/em.22342. [Epub ahead of print]

Next-Generation Genotoxicology: Using Modern Sequencing Technologies to Assess Somatic Mutagenesis and Cancer Risk.

Author information

1
Department of Medicine, Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
2
TwinStrand Biosciences, Seattle, Washington.
3
Department of Pathology, University of Washington, Seattle, Washington.

Abstract

Mutations have a profound effect on human health, particularly through an increased risk of carcinogenesis and genetic disease. The strong correlation between mutagenesis and carcinogenesis has been a driving force behind genotoxicity research for more than 50 years. The stochastic and infrequent nature of mutagenesis makes it challenging to observe and to study. Indeed, decades have been spent developing increasingly sophisticated assays and methods to study these low frequency genetic errors, in hopes of better predicting which chemicals may be carcinogens, understanding their mode of action, and informing guidelines to prevent undue human exposure. While effective, widely used genetic selection-based technologies have a number of limitations that have hampered major advancements in the field of genotoxicity. Emerging new tools, in the form of enhanced next generation sequencing platforms and methods, are changing this paradigm. In this review, we discuss rapidly evolving sequencing tools and technologies, such as error-corrected sequencing and single cell analysis, that we anticipate will fundamentally reshape the field. In addition, we consider a variety emerging applications for these new technologies, including the detection of DNA adducts, inference of mutational processes based on genomic site and local sequence contexts, and evaluation of genome engineering fidelity, as well as other cutting-edge challenges for the next 50 years of environmental and molecular mutagenesis research. This article is protected by copyright. All rights reserved.

KEYWORDS:

Chemical carcinogenesis; cancer risk assessment; consensus sequencing; error-corrected NGS; in vivo mutation; single molecule sequencing; single-cell sequencing

PMID:
31595553
DOI:
10.1002/em.22342

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