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.
Chromothripsis scars the genome when localized chromosome shattering and repair occurs in a one-off catastrophe. Outcomes of this process are detectable as massive DNA rearrangements affecting one or ...a few chromosomes. Although recent findings suggest a crucial role of chromothripsis in cancer development, the reproducible inference of this process remains challenging, requiring that cataclysmic one-off rearrangements be distinguished from localized lesions that occur progressively. We describe conceptual criteria for the inference of chromothripsis, based on ruling out the alternative hypothesis that stepwise rearrangements occurred. Robust means of inference may facilitate in-depth studies on the impact of, and the mechanisms underlying, chromothripsis.
Telomere crisis occurs during tumorigenesis when depletion of the telomere reserve leads to frequent telomere fusions. The resulting dicentric chromosomes have been proposed to drive genome ...instability. Here, we examine the fate of dicentric human chromosomes in telomere crisis. We observed that dicentric chromosomes invariably persisted through mitosis and developed into 50–200 μm chromatin bridges connecting the daughter cells. Before their resolution at 3–20 hr after anaphase, the chromatin bridges induced nuclear envelope rupture in interphase, accumulated the cytoplasmic 3′ nuclease TREX1, and developed RPA-coated single stranded (ss) DNA. CRISPR knockouts showed that TREX1 contributed to the generation of the ssDNA and the resolution of the chromatin bridges. Post-crisis clones showed chromothripsis and kataegis, presumably resulting from DNA repair and APOBEC editing of the fragmented chromatin bridge DNA. We propose that chromothripsis in human cancer may arise through TREX1-mediated fragmentation of dicentric chromosomes formed in telomere crisis.
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•Dicentric chromosomes formed during telomere crisis do not break in mitosis•Cells with dicentrics develop chromatin bridges that induce nuclear envelope rupture•The TREX1 3′ nuclease generates ssDNA in the bridges and facilitates their resolution•Post-telomere crisis cells often show chromothripsis and kataegis
During telomere crisis, dicentric chromosomes form long chromatin bridges that induce nuclear envelope rupture. Nucleolytic attack of the dicentric chromosomes generates extensive ssDNA and leads to bridge breakage, which may contribute to the occurrence of chromothripsis and kataegis in cancer genomes.
This paper analyses the potential environmental impacts and economic viability of producing biodiesel from microalgae grown in ponds. A comparative Life Cycle Assessment (LCA) study of a notional ...production system designed for Australian conditions was conducted to compare biodiesel production from algae (with three different scenarios for carbon dioxide supplementation and two different production rates) with canola and ULS (ultra-low sulfur) diesel. Comparisons of GHG (greenhouse gas) emissions (g CO
2-e/t
km) and costs (¢/t
km) are given. Algae GHG emissions (−27.6 to 18.2) compare very favourably with canola (35.9) and ULS diesel (81.2). Costs are not so favourable, with algae ranging from 2.2 to 4.8, compared with canola (4.2) and ULS diesel (3.8). This highlights the need for a high production rate to make algal biodiesel economically attractive.
Breakthroughs in gene-sequencing methods and bioinformatics have ushered in a new era in cancer diagnosis and management. Powerful analytic tools are beginning to improve cancer nosology and ...facilitate the discovery of genetic defects in tumor cells that can be exploited for treatment and the monitoring of disease regression and progression. This article is accompanied by an explanatory video, an illustrated glossary, and an audio interview with the author.
Evolution of the cancer genome YATES, Lucy R; CAMPBELL, Peter J
Nature reviews. Genetics,
11/2012, Volume:
13, Issue:
11
Journal Article
Peer reviewed
Open access
The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is ...providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces that act on nascent cancer clones as they evolve and have shown insight into the mutational processes that generate genetic variation. Here we review our emerging understanding of the dynamic evolution of the cancer genome and of the implications for basic cancer biology and the development of antitumour therapy.
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.
The genome of a cancer cell carries somatic mutations that are the cumulative consequences of the DNA damage and repair processes operative during the cellular lineage between the fertilized egg and ...the cancer cell. Remarkably, these mutational processes are poorly characterized. Global sequencing initiatives are yielding catalogs of somatic mutations from thousands of cancers, thus providing the unique opportunity to decipher the signatures of mutational processes operative in human cancer. However, until now there have been no theoretical models describing the signatures of mutational processes operative in cancer genomes and no systematic computational approaches are available to decipher these mutational signatures. Here, by modeling mutational processes as a blind source separation problem, we introduce a computational framework that effectively addresses these questions. Our approach provides a basis for characterizing mutational signatures from cancer-derived somatic mutational catalogs, paving the way to insights into the pathogenetic mechanism underlying all cancers.
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► Theoretical model describing mutational processes operative in cancer genomes ► Computational framework for deciphering signatures of mutational processes ► Extensive evaluation of the computational framework with simulated data ► Application to mutational catalogs of breast cancer genomes and exomes
Stratton and colleagues provide a theoretical model and computational framework that bridge the gap between mutational catalogs derived from cancer genomes and the signatures of mutational processes contained in these catalogs. They extensively evaluate their framework with simulated and real data, demonstrating that it allows incorporation of a wide variety of different mutation types. The framework is robust to a large range of different parameters and applicable to mutational catalogs derived from genome and exome sequencing.
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