Somatic mutation in cancer and normal cells Martincorena, Iñigo; Campbell, Peter J.
Science (American Association for the Advancement of Science),
09/2015, Volume:
349, Issue:
6255
Journal Article
Peer reviewed
Spontaneously occurring mutations accumulate in somatic cells throughout a person's lifetime. The majority of these mutations do not have a noticeable effect, but some can alter key cellular ...functions. Early somatic mutations can cause developmental disorders, whereas the progressive accumulation of mutations throughout life can lead to cancer and contribute to aging. Genome sequencing has revolutionized our understanding of somatic mutation in cancer, providing a detailed view of the mutational processes and genes that drive cancer. Yet, fundamental gaps remain in our knowledge of how normal cells evolve into cancer cells. We briefly summarize a number of the lessons learned over 5 years of cancer genome sequencing and discuss their implications for our understanding of cancer progression and aging.
Cancer develops as a result of somatic mutation and clonal selection, but quantitative measures of selection in cancer evolution are lacking. We adapted methods from molecular evolution and applied ...them to 7,664 tumors across 29 cancer types. Unlike species evolution, positive selection outweighs negative selection during cancer development. On average, <1 coding base substitution/tumor is lost through negative selection, with purifying selection almost absent outside homozygous loss of essential genes. This allows exome-wide enumeration of all driver coding mutations, including outside known cancer genes. On average, tumors carry ∼4 coding substitutions under positive selection, ranging from <1/tumor in thyroid and testicular cancers to >10/tumor in endometrial and colorectal cancers. Half of driver substitutions occur in yet-to-be-discovered cancer genes. With increasing mutation burden, numbers of driver mutations increase, but not linearly. We systematically catalog cancer genes and show that genes vary extensively in what proportion of mutations are drivers versus passengers.
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•Unlike the germline, somatic cells evolve predominantly by positive selection•Nearly all (∼99%) coding mutations are tolerated and escape negative selection•Exome-wide estimates of the total number of driver coding mutations per tumor•Half of the coding driver mutations occur outside of known cancer genes
Adapting an evolutionary genomics approach to cancer highlights a limited impact of negative selection on cancer genomes and significant variations in the proportion of coding driver mutations per tumor among different tumor types.
Cancer genomics has produced extensive information on cancer-associated genes, but the number and specificity of cancer-driver mutations remains a matter of debate. We constructed a bipartite network ...in which 7,665 tumors from 30 cancer types are connected via shared mutations in 198 previously identified cancer genes. We show that about 27% of the tumors can be assigned to statistically supported modules, most of which encompass one or two cancer types. The rest of the tumors belong to a diffuse network component suggesting lower gene specificity of driver mutations. Linear regression of themutational loads in cancer geneswas used to estimate the number of drivers required for the onset of different cancers. The mean number of drivers in known cancer genes is approximately two, with a range of one to five. Cancers that are associated with modules had more drivers than those from the diffuse network component, suggesting that unidentified and/or interchangeable drivers exist in the latter.
The extent to which cells in normal tissues accumulate mutations throughout life is poorly understood. Some mutant cells expand into clones that can be detected by genome sequencing. We mapped mutant ...clones in normal esophageal epithelium from nine donors (age range, 20 to 75 years). Somatic mutations accumulated with age and were caused mainly by intrinsic mutational processes. We found strong positive selection of clones carrying mutations in 14 cancer genes, with tens to hundreds of clones per square centimeter. In middle-aged and elderly donors, clones with cancer-associated mutations covered much of the epithelium, with
and
mutations affecting 12 to 80% and 2 to 37% of cells, respectively. Unexpectedly, the prevalence of
mutations in normal esophagus was several times higher than in esophageal cancers. These findings have implications for our understanding of cancer and aging.
Performing a statistical test requires a null hypothesis. In cancer genomics, a key challenge is the fast generation of accurate somatic mutational landscapes that can be used as a realistic null ...hypothesis for making biological discoveries.
Here we present SigProfilerSimulator, a powerful tool that is capable of simulating the mutational landscapes of thousands of cancer genomes at different resolutions within seconds. Applying SigProfilerSimulator to 2144 whole-genome sequenced cancers reveals: (i) that most doublet base substitutions are not due to two adjacent single base substitutions but likely occur as single genomic events; (ii) that an extended sequencing context of ± 2 bp is required to more completely capture the patterns of substitution mutational signatures in human cancer; (iii) information on false-positive discovery rate of commonly used bioinformatics tools for detecting driver genes.
SigProfilerSimulator's breadth of features allows one to construct a tailored null hypothesis and use it for evaluating the accuracy of other bioinformatics tools or for downstream statistical analysis for biological discoveries. SigProfilerSimulator is freely available at https://github.com/AlexandrovLab/SigProfilerSimulator with an extensive documentation at https://osf.io/usxjz/wiki/home/ .
A widely accepted tenet of evolutionary biology is that spontaneous mutations occur randomly with regard to their fitness effect. However, since the mutation rate varies along a genome and this ...variation can be subject to selection, organisms might evolve lower mutation rates at loci where mutations are most deleterious or increased rates where mutations are most needed. In fact, mechanisms of targeted hypermutation are known in organisms ranging from bacteria to humans. Here we review the main forces driving the evolution of local mutation rates and identify the main limiting factors. Both targeted hyper‐ and hypomutation can evolve, although the former is restricted to loci under very frequent positive selection and the latter is severely limited by genetic drift. Nevertheless, we show how an association of repair with transcription or chromatin‐associated proteins could overcome the drift limit and lead to non‐random hypomutation along the genome in most organisms.
Editor's suggested further reading in BioEssays Stress‐induced mutation via DNA breaks in Escherichia coli: A molecular mechanism with implications for evolution and medicine
Mutations are traditionally assumed to occur randomly with respect to fitness. However, mutation rates can vary along a genome and this variation can be evolutionarily optimized under certain conditions. Here we discuss the conditions and mechanisms by which selectively favourable mutational cold and hot spots can evolve along a genome.
Clonal dynamics and mutation burden in healthy human prostate epithelium are relevant to prostate cancer. We sequenced whole genomes from 409 microdissections of normal prostate epithelium across 8 ...donors, using phylogenetic reconstruction with spatial mapping in a 59-year-old man’s prostate to reconstruct tissue dynamics across the lifespan. Somatic mutations accumulate steadily at ∼16 mutations/year/clone, with higher rates in peripheral than peri-urethral regions. The 24–30 independent glandular subunits are established as rudimentary ductal structures during fetal development by 5–10 embryonic cells each. Puberty induces formation of further side and terminal branches by local stem cells disseminated throughout the rudimentary ducts during development. During adult tissue maintenance, clonal expansions have limited geographic scope and minimal migration. Driver mutations are rare in aging prostate epithelium, but the one driver we did observe generated a sizable intraepithelial clonal expansion. Leveraging unbiased clock-like mutations, we define prostate stem cell dynamics through fetal development, puberty, and aging.
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•Somatic mutations accumulate with age in normal human prostate at ∼16/year/cell•5–10 embryonic cells found each of the 24–30 ductal subunits in fetal development•Puberty acts on local stem cells in ductal units to increase branching complexity•In adulthood, clones are small and spatially limited and have few driver mutations
Using spontaneously occurring somatic mutations as lineage marks, Campbell, Heer, and colleagues define the stem cell dynamics of normal human prostate epithelium through fetal development, puberty, adulthood, and aging.
Information processing in the human brain arises from both interactions between adjacent areas and from distant projections that form distributed brain systems. Here we map interactions across ...different spatial scales by estimating the degree of intrinsic functional connectivity for the local (<or=14 mm) neighborhood directly surrounding brain regions as contrasted with distant (>14 mm) interactions. The balance between local and distant functional interactions measured at rest forms a map that separates sensorimotor cortices from heteromodal association areas and further identifies regions that possess both high local and distant cortical-cortical interactions. Map estimates of network measures demonstrate that high local connectivity is most often associated with a high clustering coefficient, long path length, and low physical cost. Task performance changed the balance between local and distant functional coupling in a subset of regions, particularly, increasing local functional coupling in regions engaged by the task. The observed properties suggest that the brain has evolved a balance that optimizes information-processing efficiency across different classes of specialized areas as well as mechanisms to modulate coupling in support of dynamically changing processing demands. We discuss the implications of these observations and applications of the present method for exploring normal and atypical brain function.
A central tenet in evolutionary theory is that mutations occur randomly with respect to their value to an organism; selection then governs whether they are fixed in a population. This principle has ...been challenged by long-standing theoretical models predicting that selection could modulate the rate of mutation itself. However, our understanding of how the mutation rate varies between different sites within a genome has been hindered by technical difficulties in measuring it. Here we present a study that overcomes previous limitations by combining phylogenetic and population genetic techniques. Upon comparing 34 Escherichia coli genomes, we observe that the neutral mutation rate varies by more than an order of magnitude across 2,659 genes, with mutational hot and cold spots spanning several kilobases. Importantly, the variation is not random: we detect a lower rate in highly expressed genes and in those undergoing stronger purifying selection. Our observations suggest that the mutation rate has been evolutionarily optimized to reduce the risk of deleterious mutations. Current knowledge of factors influencing the mutation rate—including transcription-coupled repair and context-dependent mutagenesis—do not explain these observations, indicating that additional mechanisms must be involved. The findings have important implications for our understanding of evolution and the control of mutations.
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