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.
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.
Analysis of mutational signatures is becoming routine in cancer genomics, with implications for pathogenesis, classification, prognosis, and even treatment decisions. However, the field lacks a ...consensus on analysis and result interpretation. Using whole-genome sequencing of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and acute myeloid leukemia, we compare the performance of public signature analysis tools. We describe caveats and pitfalls of de novo signature extraction and fitting approaches, reporting on common inaccuracies: erroneous signature assignment, identification of localized hyper-mutational processes, overcalling of signatures. We provide reproducible solutions to solve these issues and use orthogonal approaches to validate our results. We show how a comprehensive mutational signature analysis may provide relevant biological insights, reporting evidence of c-AID activity among unmutated CLL cases or the absence of BRCA1/BRCA2-mediated homologous recombination deficiency in a MM cohort. Finally, we propose a general analysis framework to ensure production of accurate and reproducible mutational signature data.
The authors identify 11 discrete genetic subsets of acute myeloid leukemia on the basis of the expression and coexpression of particular mutations. Prospective studies may elucidate distinct ...approaches to their management.
Acute myeloid leukemia (AML) is characterized by clonal expansion of undifferentiated myeloid precursors, resulting in impaired hematopoiesis and bone marrow failure. Although many patients with AML have a response to induction chemotherapy, refractory disease is common, and relapse represents the major cause of treatment failure.
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Cancer develops from somatically acquired driver mutations, which account for the myriad biologic and clinical complexities of the disease. A classification of cancers that is based on causality is likely to be durable, reproducible, and clinically relevant. This is already evident in the case of AML, for which there has been a progressive shift from . . .
All normal somatic cells are thought to acquire mutations, but understanding of the rates, patterns, causes and consequences of somatic mutations in normal cells is limited. The uterine endometrium ...adopts multiple physiological states over a lifetime and is lined by a gland-forming epithelium
. Here, using whole-genome sequencing, we show that normal human endometrial glands are clonal cell populations with total mutation burdens that increase at about 29 base substitutions per year and that are many-fold lower than those of endometrial cancers. Normal endometrial glands frequently carry 'driver' mutations in cancer genes, the burden of which increases with age and decreases with parity. Cell clones with drivers often originate during the first decades of life and subsequently progressively colonize the epithelial lining of the endometrium. Our results show that mutational landscapes differ markedly between normal tissues-perhaps shaped by differences in their structure and physiology-and indicate that the procession of neoplastic change that leads to endometrial cancer is initiated early in life.
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.
How somatic mutations accumulate in normal cells is central to understanding cancer development but is poorly understood. We performed ultradeep sequencing of 74 cancer genes in small (0.8 to 4.7 ...square millimeters) biopsies of normal skin. Across 234 biopsies of sun-exposed eyelid epidermis from four individuals, the burden of somatic mutations averaged two to six mutations per megabase per cell, similar to that seen in many cancers, and exhibited characteristic signatures of exposure to ultraviolet light. Remarkably, multiple cancer genes are under strong positive selection even in physiologically normal skin, including most of the key drivers of cutaneous squamous cell carcinomas. Positively selected mutations were found in 18 to 32% of normal skin cells at a density of ∼140 driver mutations per square centimeter. We observed variability in the driver landscape among individuals and variability in the sizes of clonal expansions across genes. Thus, aged sun-exposed skin is a patchwork of thousands of evolving clones with over a quarter of cells carrying cancer-causing mutations while maintaining the physiological functions of epidermis.
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