Clock-like mutational processes in human somatic cells

Clock-like mutational processes in human somatic cells

2015 December ; 47(12): 1402–1407. doi:10.1038/ng.3441. | Ludmil B. Alexandrov, Philip H. Jones, David C. Wedge, Julian E. Sale, Peter J. Campbell, Serena Nik-Zainal, Michael R. Stratton
This study investigates clock-like mutational processes in human somatic cells by analyzing mutations from 10,250 cancer genomes across 36 cancer types. Two mutational signatures, signatures 1 and 5, exhibit clock-like properties, showing a correlation between mutation numbers and age of diagnosis. Signature 1, primarily associated with deamination of 5-methylcytosine at CpG dinucleotides, has a higher mutation rate in tissues with high mitotic rates, such as the stomach and colorectum. Signature 5, which features C>T and T>C transitions, has a higher mutation rate in tissues like the kidney papillary cell and neuroblastoma. The mutation rates of these two signatures differ widely between cell types and are influenced by different biological factors. Signature 1 may be influenced by cell proliferation rate, while signature 5 may be activated by non-clock-like factors or during neoplastic transformation. The study provides the first survey of clock-like mutational processes in human somatic cells and suggests that these processes contribute to the accumulation of mutations in normal cells over a lifetime.This study investigates clock-like mutational processes in human somatic cells by analyzing mutations from 10,250 cancer genomes across 36 cancer types. Two mutational signatures, signatures 1 and 5, exhibit clock-like properties, showing a correlation between mutation numbers and age of diagnosis. Signature 1, primarily associated with deamination of 5-methylcytosine at CpG dinucleotides, has a higher mutation rate in tissues with high mitotic rates, such as the stomach and colorectum. Signature 5, which features C>T and T>C transitions, has a higher mutation rate in tissues like the kidney papillary cell and neuroblastoma. The mutation rates of these two signatures differ widely between cell types and are influenced by different biological factors. Signature 1 may be influenced by cell proliferation rate, while signature 5 may be activated by non-clock-like factors or during neoplastic transformation. The study provides the first survey of clock-like mutational processes in human somatic cells and suggests that these processes contribute to the accumulation of mutations in normal cells over a lifetime.
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