Genome-wide mutational signatures of immunological diversification in normal lymphocytes

Machado, Heather E.; Mitchell, Emily; Øbro, Nina Friesgaard; Kübler, Kirsten; Davies, Megan; Maura, Francesco; Leongamornlert, Daniel; Sanders, Mathijs A.; Cagan, Alex; McDonald, Craig; Belmonte, Miriam; Shepherd, Mairi; Osborne, Robert J.; Mahbubani, Krishnaa; Laurenti, Elisa; Green, A; Getz, Gad; Polak, Paz; Saeb‐Parsy, Kourosh; Hodson, Daniel J.; Kent, David; Campbell, Peter J.

doi:10.1101/2021.04.29.441939

Cited by 5 publications

(8 citation statements)

References 100 publications

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“…Mutations attributed to signature SBS9 are due to DNA damage caused by polymerase eta activity and were observed only in Burkitt's lymphoma (BL) in this cohort. As previously described, SBS9 activity is found in BL with immunoglobulin gene hypermutations 36 (Supp. Fig.…”

supporting

confidence: 55%

Comprehensive analysis of mutational signatures in pediatric cancers

Thatikonda

Islam²,

Jones

et al. 2021

Preprint

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Analysis of mutational signatures can reveal the underlying molecular mechanisms of the processes that have imprinted the somatic mutations found in a cancer genome. Here, we present a pan-cancer mutational signatures analysis of single base substitutions (SBS) and small insertion and deletions (ID) in pediatric cancers encompassing 537 whole genome sequenced tumors from 20 molecularly defined cancer subtypes. We identified only a small number of mutational signatures active in pediatric cancers when compared to the previously analyzed adult cancers. Further, we report a significant difference in the proportion of pediatric tumors which show homologous recombination repair defect signature SBS3 compared to prior analyses. Correlating genomic alterations with signature activities, we identified an association of TP53 mutation status with substitution signatures SBS2, SBS8, SBS13 and indel signatures ID2 and ID9, as well as chromothripsis associated with SBS8, SBS40 and ID9. This analysis provides a systematic overview of COSMIC v.3 SBS and ID mutational signatures active across pediatric cancers, which is highly relevant for understanding tumor biology as well as enabling future research in defining biomarkers of treatment response.

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supporting

confidence: 55%

Comprehensive analysis of mutational signatures in pediatric cancers

Thatikonda

Islam²,

Jones

et al. 2021

Preprint

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“…Prostatic epithelium (Grossmann et al, 2021;Moore et al, 2021). HSPCs (Osorio et al, 2018;Abascal et al, 2021;Machado et al, 2021;Mitchell et al, 2021). Satellite cells (Franco et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

The Dynamics of Somatic Mutagenesis During Life in Humans

2021

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From conception to death, human cells accumulate somatic mutations in their genomes. These mutations can contribute to the development of cancer and non-malignant diseases and have also been associated with aging. Rapid technological developments in sequencing approaches in the last few years and their application to normal tissues have greatly advanced our knowledge about the accumulation of these mutations during healthy aging. Whole genome sequencing studies have revealed that there are significant differences in mutation burden and patterns across tissues, but also that the mutation rates within tissues are surprisingly constant during adult life. In contrast, recent lineage-tracing studies based on whole-genome sequencing have shown that the rate of mutation accumulation is strongly increased early in life before birth. These early mutations, which can be shared by many cells in the body, may have a large impact on development and the origin of somatic diseases. For example, cancer driver mutations can arise early in life, decades before the detection of the malignancy. Here, we review the recent insights in mutation accumulation and mutagenic processes in normal tissues. We compare mutagenesis early and later in life and discuss how mutation rates and patterns evolve during aging. Additionally, we outline the potential impact of these mutations on development, aging and disease.

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“…Using the methods described above, it has been determined that the genomes of healthy cells gradually accumulate mutations during life ( Blokzijl et al, 2016 ; Lee-Six et al, 2018 ; Osorio et al, 2018 ; Machado et al, 2021 ). This rate varies between ∼40 mutations per year in liver, small intestine, and colon, while hematopoietic stem cells and muscle stem cells are on the lower end with about 13–15 novel mutations each year ( Franco et al, 2018 ; Lee-Six et al, 2018 ; Osorio et al, 2018 ).…”

Section: Detection Of Mutations Induced By Environmental Genotoxinsmentioning

confidence: 99%

“…This observation suggests that the number of genotoxin-induced mutations does not necessarily has to correlate with the dose of exposure. In addition to melanocytes, the mutational signatures attributed to UV-damage have also been observed in skin-residing lymphocytes ( Machado et al, 2021 ) and sporadically in T-cell lymphoma ( Jones et al, 2021 ), pointing to a past exposure to UV-radiation.…”

Section: Detection Of Mutations Induced By Environmental Genotoxinsmentioning

confidence: 99%

“…Most of the mutations that accumulate in healthy tissues during normal ageing are induced by endogenous mutagenic processes ( Blokzijl et al, 2016 ; Franco et al, 2018 ; Lee-Six et al, 2018 ; Lodato et al, 2018 ; Osorio et al, 2018 ; Franco et al, 2019 ; Lee-Six et al, 2019 ; Machado et al, 2021 ). This notion potentially explains why aging is the main risk factor for developing cancer ( Edwards et al, 2002 ; Tomasetti and Vogelstein, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

2021

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During life, the DNA of our cells is continuously exposed to external damaging processes. Despite the activity of various repair mechanisms, DNA damage eventually results in the accumulation of mutations in the genomes of our cells. Oncogenic mutations are at the root of carcinogenesis, and carcinogenic agents are often highly mutagenic. Over the past decade, whole genome sequencing data of healthy and tumor tissues have revealed how cells in our body gradually accumulate mutations because of exposure to various mutagenic processes. Dissection of mutation profiles based on the type and context specificities of the altered bases has revealed a variety of signatures that reflect past exposure to environmental mutagens, ranging from chemotherapeutic drugs to genotoxic gut bacteria. In this review, we discuss the latest knowledge on somatic mutation accumulation in human cells, and how environmental mutagenic factors further shape the mutation landscapes of tissues. In addition, not all carcinogenic agents induce mutations, which may point to alternative tumor-promoting mechanisms, such as altered clonal selection dynamics. In short, we provide an overview of how environmental factors induce mutations in the DNA of our healthy cells and how this contributes to carcinogenesis. A better understanding of how environmental mutagens shape the genomes of our cells can help to identify potential preventable causes of cancer.

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Genome-wide mutational signatures of immunological diversification in normal lymphocytes

Cited by 5 publications

References 100 publications

Comprehensive analysis of mutational signatures in pediatric cancers

Comprehensive analysis of mutational signatures in pediatric cancers

The Dynamics of Somatic Mutagenesis During Life in Humans

The Mutagenic Impact of Environmental Exposures in Human Cells and Cancer: Imprints Through Time

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