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. 2015 Dec;47(12):1402-7.
doi: 10.1038/ng.3441. Epub 2015 Nov 9.

Clock-like mutational processes in human somatic cells

Ludmil B Alexandrov  1   2   3 , Philip H Jones  1   4 , David C Wedge  1 , Julian E Sale  5 , Peter J Campbell  1   6 , Serena Nik-Zainal  1   7 , Michael R Stratton  1
Affiliations

Clock-like mutational processes in human somatic cells

Ludmil B Alexandrov et al. Nat Genet. 2015 Dec.

Abstract

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.

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Figures

Figure 1
Figure 1. A model for the accumulation of somatic mutations in cancers
(a) Cell lineages leading from fertilised egg to cancer cell in five different individuals with cancer; A, B, C, D and E. Orange: embryonic/foetal cell divisions; blue, postnatal divisions of normal cells; brown, cell divisions post-neoplastic change. (b) Accumulation of somatic mutations due to clock-like and non-clock-like mutational signatures in the same five patients. The correlation between age and somatic mutations due to a clock-like mutational process operating in normal postnatal cells is detectable using the mutations found in cancers, with the rate relatively unaffected, if the number of mutations acquired during the embryonic/foetal and neoplastic phases is limited. Note that this figure is provided as a simple illustration of the activity of clock-like mutational processes and it is not intended to be a realistic representation of actual cancer samples. In reality, the numbers of cellular divisions will be tissue dependent and the numbers of neoplastic mutations may be many folds of magnitude higher.
Figure 2
Figure 2. Patterns of mutational signatures 1 and 5
The signatures are displayed according to the 96 substitution classification defined by the substitution class and sequence context immediately 5′ and 3′ to the mutated base. The probability bars for the six substitution classes are displayed in different colours. The mutation types are on the X-axes, whereas Y-axes show the percentage of mutations in the signature attributed to each mutation type. Signatures are displayed on the basis of the trinucleotide frequencies of the whole human genome.
Figure 3
Figure 3. Correlations between ages of cancer diagnosis and mutations attributed to signatures 1 and 5
Y-axes show numbers of somatic substitutions per gigabase attributed to either signature 1 or signature 5, while X-axes show ages of cancer diagnosis. Each panel corresponds to a cancer type and panels are sorted in a decreasing order of the estimated slopes for signature 1. Each dot represents the median number of somatic mutations for all cancers of a given age. Red and green lines show best estimates for the slopes, i.e., mutation rates, of signature 1 and 5 respectively. 95% confidence intervals for the slopes are shown in lighter green and lighter red shading for signatures 1 and 5 respectively. Note that for several cancer types slopes extend far beyond the available data points; this representation is not intended to be a prediction but rather it is done for consistent presentation across all panels in the figure. Slopes and p-values are also provided in Table 1. Panels showing mutational burdens in individual samples in each of the cancer types are provided in Supplementary Figure 3. Furthermore, a supplementary figure depicting the slopes for each cancer type is provided (Supplementary Figures 8 through 43).
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