Clock-like mutational processes in human somatic cells

• Published in: Nature genetics Vol. 47; no. 12; pp. 1402 - 1407
• Main Authors: Alexandrov, Ludmil B, Jones, Philip H, Wedge, David C, Sale, Julian E, Campbell, Peter J, Nik-Zainal, Serena, Stratton, Michael R
• Format: Journal Article Conference Proceeding
• Language: English
• Published: New York Nature Publishing Group US 01.12.2015; Nature Publishing Group
• Subjects: 45; 45/70; 631/114; 631/208/212; 692/699/67; Age; Agriculture; analysis; Animal Genetics and Genomics; Basic Biological Sciences; Biological Clocks - genetics; Biological Science; Biomedicine; Cancer Research; Cell Lineage - genetics; Cell Transformation, Neoplastic - genetics; Cellular control mechanisms; Datasets; Embryo, Mammalian - cytology; Embryo, Mammalian - metabolism; Gene Expression Regulation, Neoplastic; Gene Function; Gene mutations; Genetic aspects; Genetic research; Genome, Human; Genomes; Health aspects; Human Genetics; Humans; Identification and classification; Laboratories; Medical research; Mutation; Mutation - genetics; Mutation Rate; Neoplasms - classification; Neoplasms - genetics; Rodents; Scholarships & fellowships; Somatic cells; Websites
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3441

Ludmil Alexandrov, Michael Stratton and colleagues analyze 10,250 human cancer genomes from 36 cancer types to identify mutational signatures with clock-like properties. They identify two signatures with different mutation rates that show a correlation between age at diagnosis and number of mutations in most cancer types. 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.