Mechanisms underlying mutational signatures in human cancers

Helleday, Thomas; Eshtad, Saeed; Nik-Zainal, Serena

doi:10.1038/nrg3729

Cited by 717 publications

(702 citation statements)

References 116 publications

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“…It seems unlikely that the observed variation in signature 1 mutation rate between cell types is simply due to differences in the extent of CpG methylation, because this is similar in most cell types 3,8 , although it could be due to differences in rates of cytosine deamination and/or T excision at T/G mismatches by thymine DNA glycosylase or mismatch repair.…”

Section: Resultsmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

“…Different mutational processes generate distinct combinations of mutation types in cancer genomes 2,3 . These characteristic imprints of mutational processes have been termed "mutational signatures".…”

Section: Introductionmentioning

confidence: 99%

Clock-like mutational processes in human somatic cells

et al. 2015

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“…The "mutational portraits" of different cancers are composed from differing quotients of many distinct mutational processes, and the snapshot at the point a tumor sample is sequenced is an accumulation of the history of these processes and a combination across the heterogeneity of the tumor sample [85]. Extensive sequencing across many samples is required so that recurrent and overlapping mutational processes can be teased apart into their constituent signatures.…”

Section: Box 2: Extracting Mutation Signaturesmentioning

confidence: 99%

APOBEC3 genes: retroviral restriction factors to cancer drivers

Henderson

Fenton

2015

Trends in Molecular Medicine

102

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Abstract:The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Now recent advances in cancer genomics together with biochemical characterization of the APOBEC3 enzymes have implicated at least two family members in somatic mutagenesis during tumor development. Here we review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk. Powered by Editorial Manager® and ProduXion Manager® from Aries Systems CorporationHenderson and Fenton: highlights AbstractThe APOBEC3 cytosine deaminases play key roles in innate immunity through their

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“…In the past few years, there are 30 patterns of mutational signatures be found across the spectrum of human cancer types from many large‐scale analyses,43, 44, 45, 46, 47 including 11 types of signatures found in gastric cancer. We observed a significant association between rs1679709 and the weights of COSMIC Signature 15.…”

Section: Discussionmentioning

confidence: 99%

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

et al. 2018

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Genome‐wide association studies have identified several germline variants in gastric cancer. Meanwhile, sequencing studies have characterized extensive somatic alterations that arise during gastric carcinogenesis. However, the relationship between the germline variants and somatic alterations is still unclear in gastric cancer. A total of 11 susceptibility loci and 276 driver genes of gastric cancer were determined based on previous studies and publicly available database. An enrichment analysis was made to detect whether driver genes were enriched in susceptibility regions. Besides, we performed a pathway enrichment analysis to find common‐enrich pathways of cancer driver genes and susceptibility genes. Finally, on the basis of the gastric cancer samples and data from TCGA STAD project, we evaluated the associations between susceptibility loci and somatic alterations. Enrichment analysis showed that gastric cancer susceptibility genes were more likely to be enriched in driver genes than in all the genes (P = .05). The susceptibility genes and driver genes were commonly enriched in 8 biological pathways. Gastric cancer susceptibility locus of rs2285947 was associated with truncation mutation within Signaling by PDGF pathway (OR = 0.26, 95%CI: 0.12‐0.55, P = 3.93 × 10−4). The rs1679709 was connected with COSMIC Signature15 (P = .026). Moreover, rs1679709 was also associated with copy number values of RFC4 which is related to Signature15. These results provide evidence for the relationship between germline variants and somatic alterations, which facilitate understanding the interactive mechanism of germline variations with somatic alterations in gastric cancer development.

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Mechanisms underlying mutational signatures in human cancers

Cited by 717 publications

References 116 publications

Clock-like mutational processes in human somatic cells

Clock-like mutational processes in human somatic cells

APOBEC3 genes: retroviral restriction factors to cancer drivers

Germline genetic variants were interactively associated with somatic alterations in gastric cancer

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