The mutational signature profile of known and suspected human carcinogens in mice

Riva, Laura; Pandiri, Arun R.; Li, Yun R.; Droop, Alastair; Hewinson, James; Quail, Michael A.; Iyer, Vivek; Shepherd, Rebecca; Herbert, Ronald A.; Campbell, Peter J.; Sills, Robert C.; Alexandrov, Ludmil B.; Balmain, Allan; Adams, David J.

doi:10.1038/s41588-020-0692-4

Cited by 96 publications

(63 citation statements)

References 35 publications

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“…Our results suggest non-progressing BE resembles aging normal tissue, which undergoes stochastic alterations and selection in cancer-associated genes that confer survival advantages, and maintains the requisite cell-and tissue-based mechanisms that prevent development of cancer. This hypothesis is supported by our data showing very similar mutation signatures, mutation loads and ESAD associated gene alterations in both NCO and CO, as well as by the results of mutagenesis analyses in mice 63 .…”

Section: Discussionsupporting

confidence: 86%

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Paulson

Galipeau

Oman

et al. 2021

Preprint

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While the genomes of normal tissues undergo dynamic changes over time, little is understood about the temporal-spatial dynamics of genomes in premalignant tissues that progress to cancer compared to those that remain cancer-free. Here we use whole genome sequencing to contrast genomic alterations in 427 longitudinal samples from 40 patients with stable Barrett’s esophagus compared to 40 Barrett’s patients who progressed to esophageal adenocarcinoma (ESAD). We show the same somatic mutational processes were active in Barrett’s tissue regardless of outcome, with high levels of mutation, ESAD gene and focal chromosomal alterations, and similar mutational signatures. The critical distinction between stable Barrett’s versus those who progress to cancer is acquisition and expansion of TP53-/- cell populations having complex structural variants and high-level amplifications, which were detectable up to six years prior to a cancer diagnosis. These findings reveal the timing of common somatic genome dynamics in stable Barrett’s esophagus and define key genomic features specific to progression to esophageal adenocarcinoma, both of which are critical for cancer prevention and early detection strategies.

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Section: Discussionsupporting

confidence: 86%

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Paulson

Galipeau

Oman

et al. 2021

Preprint

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“…This could be a pure agnostic analysis of large datasets of genome instability catalogs [ 119 , 121 , 163 ], which can be also combined with prior mechanistic knowledge about different types of mutagenesis [ 120 ]. Another approach is to collect knowledge about mutational signatures in defined systems—mammalian [ 164 , 165 ] or microbial [ 133 , 135 ], and then utilize the information to build a specific statistical hypothesis for interrogating datasets of natural variants. High rates of mutation and relative ease of RNA virus genome sequencing can certainly make these approaches productive and scalable.…”

Section: Concluding Remarks and Future Questionsmentioning

confidence: 99%

From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

Kockler

Gordenin

2021

Cells

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The current SARS-CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS-CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.

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“…This could be a pure agnostic analysis of large datasets of genome instability catalogs [121,123,181], which can be also combined with prior mechanistic knowledge about different types of mutagenesis [122]. Another approach is to collect knowledge about mutational signatures in defined systems -mammalian [182,183] or microbial [138,141], and then utilize the information to build a specific statistical hypothesis for interrogating datasets of natural variants. High rates of mutation and relative ease of RNA virus genome sequencing can certainly make these approaches productive and scalable.…”

Section: Experimental Models To Define Signatures Of Environmental and Endogenous Mutagenesis In Rnamentioning

confidence: 99%

From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

Kockler

Gordenin

2021

Preprint

View full text Add to dashboard Cite

The current SARS- CoV-2 pandemic underscores the importance of understanding the evolution of RNA genomes. While RNA is subject to the formation of similar lesions as DNA, the evolutionary and physiological impacts RNA lesions have on viral genomes are yet to be characterized. Lesions that may drive the evolution of RNA genomes can induce breaks that are repaired by recombination or can cause base substitution mutagenesis, also known as base editing. Over the past decade or so, base editing mutagenesis of DNA genomes has been subject to many studies, revealing that exposure of ssDNA is subject to hypermutation that is involved in the etiology of cancer. However, base editing of RNA genomes has not been studied to the same extent. Recently hypermutation of single-stranded RNA viral genomes have also been documented though its role in evolution and population dynamics. Here, we will summarize the current knowledge of key mechanisms and causes of RNA genome instability covering areas from the RNA world theory to the SARS- CoV-2 pandemic of today. We will also highlight the key questions that remain as it pertains to RNA genome instability, mutations accumulation, and experimental strategies for addressing these questions.

show abstract

The mutational signature profile of known and suspected human carcinogens in mice

Cited by 96 publications

References 35 publications

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

Somatic whole genome dynamics of precancer in Barrett’s Esophagus

From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

From RNA World to SARS-CoV-2: The Edited Story of RNA Viral Evolution

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