Genome sequencing of normal cells reveals developmental lineages and mutational processes

Behjati, Sam; Huch, Meritxell; Boxtel, Ruben van; Karthaus, Wouter R.; Wedge, David C.; Tamuri, Asif U.; Martincorena, Iñigo; Petljak, Mia; Alexandrov, Ludmil B.; Gundem, Gunes; Tarpey, Patrick; Roerink, Sophie F.; Blokker, Joyce; Maddison, Mark; Mudie, Laura; Robinson, Ben; Nik-Zainal, Serena; Campbell, Peter J.; Goldman, Nick; Wetering, Marc van de; Cuppen, Edwin; Clevers, Hans; Stratton, Michael R.

doi:10.1038/nature13448

Cited by 334 publications

(292 citation statements)

References 29 publications

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“…Given the inherent mutagenicity of 5ClC described here, when a cell having this lesion burden replicates, it would acquire about 3.3-99 new mutations. This number represents a notable increase over the spontaneous mutation rate, estimated for mammalian cells to be on average 1.1-1.5 mutations per cell division (52,53). Given that no repair pathway specific for 5ClC has yet been described (perhaps explaining the accumulation and persistence of this lesion in the genome), it is plausible that 5ClC is an important contributor to the mutagenic burden previously observed in tissues subjected to chronic inflammation (54,55) and thus increases the probability that such tissues progress toward malignancy.…”

Section: Discussionmentioning

confidence: 99%

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Fedeles

Freudenthal

Yau

et al. 2015

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

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During chronic inflammation, neutrophil-secreted hypochlorous acid can damage nearby cells inducing the genomic accumulation of 5-chlorocytosine (5ClC), a known inflammation biomarker. Although 5ClC has been shown to promote epigenetic changes, it has been unknown heretofore if 5ClC directly perpetrates a mutagenic outcome within the cell. The present work shows that 5ClC is intrinsically mutagenic, both in vitro and, at a level of a single molecule per cell, in vivo. Using biochemical and genetic approaches, we have quantified the mutagenic and toxic properties of 5ClC, showing that this lesion caused C→T transitions at frequencies ranging from 3-9% depending on the polymerase traversing the lesion. X-ray crystallographic studies provided a molecular basis for the mutagenicity of 5ClC; a snapshot of human polymerase β replicating across a primed 5ClC-containing template uncovered 5ClC engaged in a nascent base pair with an incoming dATP analog. Accommodation of the chlorine substituent in the template major groove enabled a unique interaction between 5ClC and the incoming dATP, which would facilitate mutagenic lesion bypass. The type of mutation induced by 5ClC, the C→T transition, has been previously shown to occur in substantial amounts both in tissues under inflammatory stress and in the genomes of many inflammation-associated cancers. In fact, many sequence-specific mutational signatures uncovered in sequenced cancer genomes feature C→T mutations. Therefore, the mutagenic ability of 5ClC documented in the present study may constitute a direct functional link between chronic inflammation and the genetic changes that enable and promote malignant transformation.5-chloro-deoxycytidine | hypochlorite | myeloperoxidase | inflammatory bowel disease | carcinogenesis

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Section: Discussionmentioning

confidence: 99%

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Fedeles

Freudenthal

Yau

et al. 2015

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

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“…Such factors include the number of available samples, the number of somatic mutations in a sample, the number of mutations contributed by different mutational signatures, the similarity between the patterns of the signatures of mutational processes operative in cancer samples, as well as the computational limitations of our framework. Nevertheless, in the past three years, our framework has proven robust and has described multiple similar and validated signatures across the spectrum of human cancer [3][4][5][15][16][17][18][19][20][21][22] .…”

Section: Factors Influencing Signature Extractionmentioning

confidence: 99%

Clock-like mutational processes in human somatic cells

et al. 2015

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During the course of a lifetime somatic cells acquire mutations. Different mutational processes may contribute to the mutations accumulated in a cell, with each imprinting a mutational signature on the cell's genome. Some processes generate mutations throughout life at a constant rate in all individuals and the number of mutations in a cell attributable to these processes will be proportional to the chronological age of the person. Using mutations from 10,250 cancer genomes across 36 cancer types, we investigated clock-like mutational processes that have been operating in normal human cells. Two mutational signatures show clock-like properties. Both exhibit different mutation rates in different tissues. However, their mutation rates are not correlated indicating that the underlying processes are subject to different biological influences. For one signature, the rate of cell division may influence its mutation rate. This study provides the first survey of clock-like mutational processes operative in human somatic cells.

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“…This may be a reasonable assumption, although somatic mutations have been demonstrated in genome-wide surveys and are known to accumulate with age in mammals [328][329][330], but it is unclear how much they may contribute to normal phenotypic variation. For plants, where ample opportunity for somatic mutation exists and extensive research on genetic mosaicism has been conducted, Herrera [262] reviewed the available evidence and concluded that such genetic variation is only rarely responsible for appreciable portion of within-individual variation.…”

Section: The Central Argument: Fluctuating Asymmetry As a Measure Of mentioning

confidence: 99%

Analyzing Fluctuating Asymmetry with Geometric Morphometrics: Concepts, Methods, and Applications

2015

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Approximately two decades after the first pioneering analyses, the study of shape asymmetry with the methods of geometric morphometrics has matured and is a burgeoning field. New technology for data collection and new methods and software for analysis are widely available and have led to numerous applications in plants and animals, including humans. This review summarizes the concepts and morphometric methods for studying asymmetry of shape and size. After a summary of mathematical and biological concepts of symmetry and asymmetry, a section follows that explains the methods of geometric morphometrics and how they can be used to analyze asymmetry of biological structures. Geometric morphometric analyses not only tell how much asymmetry there is, but also provide information about the patterns of covariation in the structure under study. Such patterns of covariation in fluctuating asymmetry can provide valuable insight about the developmental basis of morphological integration, and have become important tools for evolutionary developmental biology. The genetic basis of fluctuating asymmetry has been studied from empirical and theoretical viewpoints, but serious challenges remain in this area. There are many promising areas for further research that are only little explored at present.

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Genome sequencing of normal cells reveals developmental lineages and mutational processes

Cited by 334 publications

References 29 publications

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Intrinsic mutagenic properties of 5-chlorocytosine: A mechanistic connection between chronic inflammation and cancer

Clock-like mutational processes in human somatic cells

Analyzing Fluctuating Asymmetry with Geometric Morphometrics: Concepts, Methods, and Applications

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