Clock-like mutational processes in human somatic cells

By Ludmil B. Alexandrov, P. Jones, David C. Wedge, J. Sale, Peter J. Campbell, S. Nik-Zainal, Michael R. Stratton. Nature Genetics, 2015

981 citations recorded by the source corpus.

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 operating in human somatic cells.

Subfields: Cancer Research, Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/40425cc76ec269ba8dcbe0fbcc21e8c9d073dd71

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Citations in the corpus

Uncovering novel mutational signatures by de novo extraction with SigProfilerExtractor (2020, neutral): “In scenarios 5, 6, 9, and 10 (based on COSMIC signatures SBS2, SBS7a, and SBS7b, which share speciﬁc subtypes of C>T mutations), SigProﬁlerExtractor exhibited an average F 1 score of 0.96, while the next best tools had F 1 scores 0.90 (Table S1).”
Mutational signatures associated with tobacco smoking in human cancer (2016, background): “uk/cosmic/signatures, and in previous reports (16-18)).”
Comprehensive and Integrated Genomic Characterization of Adult Soft Tissue Sarcomas. (2017, positive): “COSMIC1 and COSMIC5 are clock-like mutational processes, occurring continuously over a patient’s lifetime (Alexandrov et al., 2015), and we found their contributions to the mutational profiles to be correlated with age at diagnosis in DDLPS (Pearson correlation 0.38, p = 0.006), MFS (Pearson…”
Tissue-specific mutation accumulation in human adult stem cells during life (2016, positive): “The resulting T:G mismatch can be effectively repaired, but the mutation is incorporated if DNA replication occurs before the repair is initiated 13 .”
HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational-signatures (2017, background): “Base-substitution signatures 1 (characterized by C>T transitions at NCG, where the underlined base is mutated) and 5 (primarily characterized by C>T and T>C mutations) have previously been associated with age 47 .”
Whole-Genome and Epigenomic Landscapes of Etiologically Distinct Subtypes of Cholangiocarcinoma (2017, result): “05) as previously reported for other cancer types (41).”
Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition (2021, positive): “The complete set of COSMIC mutational signatures (v2) (Alexandrov et al., 2015) was utilized.”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, positive): “An incremental, gradual, accumulation of mutations during the life history of a tumor is evidenced by the presence of clock-like mutational signatures that correlate with the chronological age of the patient (Alexandrov et al., 2015).”
The landscape of genomic alterations across childhood cancers (2018, positive): “Signatures 16 and 18 were heterogene-ously represented within several cancer types, with signature 16 being most prominent in pilocytic astrocytomas, and signature 18, previously proposed to be associated with oxidative DNA damage and related to C > A transversions, in neuroblastomas,…”
Genomic Hallmarks and Structural Variation in Metastatic Prostate Cancer. (2018, positive): “These included de novo 1, likely identical to COSMIC signature 1 associated with spontaneous deamination of 5-methylcytosine associated with age at tumor diagnosis (Alexandrov et al., 2015), andde novo 5, present in a hypermutated samplewith deepdeletion of mutS homolog 2 (MSH2) and MSH6, mismatch r”