Overview of biological mechanisms of human carcinogens

Birkett, Nicholas; Al-Zoughool, Mustafa; Bird, Michael G.; Baan, R.A.; Zielinski, Jan M.; Krewski, Daniel

doi:10.1080/10937404.2019.1643539

Cited by 36 publications

(25 citation statements)

References 279 publications

(246 reference statements)

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“…The extent of correlation between the fold change mutation induction of the two methods (R 2 = 0.898) was encouraging given that the assays measure mutant frequency via two fundamentally different approaches. Duplex Sequencing genotypes millions of unique nucleotides to assess the proportion that are mutated whereas the plaque assay measures the proportion of phage-packaged cII genes that bear at least one mutation that sufficiently disrupts the function of the cII protein to result in phenotypic plaque formation.…”

Section: Resultsmentioning

confidence: 90%

“…The probability of cancer can be increased by carcinogens—exogenous exposures that either increase the abundance of mutations or facilitate a cell’s ability to proliferate upon selective pressures. Many chemicals induce DNA damage, thereby increasing the rate of potentially oncogenic DNA replication errors 2 . The same is true for many forms of radiation 3 .…”

Section: Introductionmentioning

confidence: 99%

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Direct Quantification of in vivo Mutagenesis and Carcinogenesis Using Duplex Sequencing

Valentine¹,

Young

Fielden

et al. 2020

Preprint

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ABSTRACTThe ability to accurately measure mutations is critical for basic research and identification of potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that are low-throughput, expensive, prolonged, and don’t fully represent other species such as humans. Next generation sequencing (NGS) is a conceptually attractive alternative for mutation detection in the DNA of any organism, however, the limit of resolution for standard NGS is poor. Technical error rates (~1×10−3) of NGS obscure the true abundance of somatic mutations, which can exist at frequencies ≤1×10−7. Using Duplex Sequencing, an extremely accurate error-corrected NGS (ecNGS) technology, we were able to detect mutations induced by 3 carcinogens in 5 tissues of 2 strains of mice within 31 days following exposure. We observed a strong correlation between mutation induction measured by Duplex Sequencing and the gold-standard transgenic rodent mutation assay. We identified exposure-specific mutation spectra of each compound through trinucleotide patterns of base substitution. We observed variation in mutation susceptibility by genomic region, as well as by DNA strand. We also identified clear early signs of carcinogenesis in a cancer-predisposed strain of mice, as evidenced by apparent clonal expansions of cells carrying an activated oncogene, less than a month after carcinogen exposure. These findings demonstrate that ecNGS is a powerful method for sensitively detecting and characterizing mutagenesis and early clonal evolutionary hallmarks of carcinogenesis. Duplex Sequencing can be broadly applied to chemical safety testing, basic mutational research, and related clinical uses.SIGNIFICANCE STATEMENTError-corrected next generation sequencing (ecNGS) can be used to rapidly detect and quantify the in vivo mutagenic impact of environmental exposures or endogenous processes in any tissue, from any species, at any genomic location. The greater speed, higher scalability, richer data outputs, as well as cross-species and cross-locus applicability of ecNGS compared to existing methods make it a powerful new tool for mutational research, regulatory safety testing, and emerging clinical applications.

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Section: Resultsmentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Direct Quantification of in vivo Mutagenesis and Carcinogenesis Using Duplex Sequencing

Valentine¹,

Young

Fielden

et al. 2020

Preprint

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show abstract

“…The probability of cancer can be increased by carcinogensexogenous exposures that either increase the abundance of mutations or facilitate a cell's ability to proliferate upon selective pressures. Many chemicals induce DNA damage, thereby increasing the rate of potentially oncogenic DNA replication errors (2). The same is true for many forms of radiation (3).…”

mentioning

confidence: 99%

Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing

Valentine

Young

Fielden

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The ability to accurately measure mutations is critical for basic research and identifying potential drug and chemical carcinogens. Current methods for in vivo quantification of mutagenesis are limited because they rely on transgenic rodent systems that are low-throughput, expensive, prolonged, and do not fully represent other species such as humans. Next-generation sequencing (NGS) is a conceptually attractive alternative for detecting mutations in the DNA of any organism; however, the limit of resolution for standard NGS is poor. Technical error rates (∼1 × 10−3) of NGS obscure the true abundance of somatic mutations, which can exist at per-nucleotide frequencies ≤1 × 10−7. Using duplex sequencing, an extremely accurate error-corrected NGS (ecNGS) technology, we were able to detect mutations induced by three carcinogens in five tissues of two strains of mice within 31 d following exposure. We observed a strong correlation between mutation induction measured by duplex sequencing and the gold-standard transgenic rodent mutation assay. We identified exposure-specific mutation spectra of each compound through trinucleotide patterns of base substitution. We observed variation in mutation susceptibility by genomic region, as well as by DNA strand. We also identified a primordial marker of carcinogenesis in a cancer-predisposed strain of mice, as evidenced by clonal expansions of cells carrying an activated oncogene, less than a month after carcinogen exposure. These findings demonstrate that ecNGS is a powerful method for sensitively detecting and characterizing mutagenesis and the early clonal evolutionary hallmarks of carcinogenesis. Duplex sequencing can be broadly applied to basic mutational research, regulatory safety testing, and emerging clinical applications.

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“…The approach described in the preceding section to identify the key characteristics of the six selected agents from Volume 100 was carried out for all 86 Group-1 agents considered by Birkett et al (2019). A summary of the key characteristics of these agents based upon mechanistic information cited in the IARC Monographs is illustrated in Figure 1.…”

Section: Key Characteristics Of 86 Group-1 Agentsmentioning

confidence: 99%

“…An in-depth analysis of these characteristics, including prevalence of each of the 10 key characteristics overall and by type agent including pharmaceuticals; biological agents; As, metals, fibers, and dusts; radiation; personal habits and indoor combustions; and chemical agents and related occupations; the multiplicity of key characteristics demonstrated by these agents; and the sources of information on the key characteristics (human in-vivo and in-vitro as well as animal invivo and in-vitro) are provided by Krewski et al (2019). Birkett et al (2019) presented a brief sensitivity analysis of the prevalence of the key characteristics incorporating mechanistic information from the updated PubMed search not cited in the IARC Monographs. (This latter analysis shows that most of the relevant mechanistic information on the 10 key characteristics of human carcinogens was captured in Sections 4 of the Monographs.…”

Section: Key Characteristics Of 86 Group-1 Agentsmentioning

confidence: 99%

Development of a database on key characteristics of human carcinogens

Al-Zoughool

Bird

Rice

et al. 2019

Journal of Toxicology and Environmental Health, Part B

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A database on mechanistic characteristics of human carcinogenic agents was developed by collecting mechanistic information on agents identified as human carcinogens (Group 1) by the International Agency for Research on Cancer (IARC) in the IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. A two-phase process is described for the construction of the database according to 24 toxicological endpoints, derived from appropriate test systems that were acquired from data obtained from the mechanisms sections of the IARC Monographs (Section 4) and a supplementary PubMed search. These endpoints were then aligned with 10 key characteristics of human carcinogens that reflect the broader attributes of these agents relating to the development of cancer in humans. The considerations involved in linking of toxicological endpoints to key characteristics are described and specific examples of the determination of key characteristics for six specific agents (tamoxifen, hepatitis B virus, arsenic, ultraviolet and solar radiation, tobacco smoking, and dioxin) are provided. Data for humans and animals were tabulated separately, as were results for in-vivo and for in-vitro sources of information. The database was constructed to support a separate analysis of the expression of these endpoints by 86 Group 1 carcinogens, in-vivo and in-vitro along with an analysis of the key characteristics of these agents. KEYWORDS human carcinogens; mechanisms of carcinogenesis; genotoxic; toxicological endpoint CONTACT Mustafa Al-Zoughool

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Overview of biological mechanisms of human carcinogens

Cited by 36 publications

References 279 publications

Direct Quantification of in vivo Mutagenesis and Carcinogenesis Using Duplex Sequencing

Direct Quantification of in vivo Mutagenesis and Carcinogenesis Using Duplex Sequencing

Direct quantification of in vivo mutagenesis and carcinogenesis using duplex sequencing

Development of a database on key characteristics of human carcinogens

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