Publications by authors named "Samuel F Bakhoum"

45 Publications

The Evolution of STING Signaling and Its Involvement in Cancer.

Trends Biochem Sci 2021 Jan 15. Epub 2021 Jan 15.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway has been primarily characterized as an inflammatory mechanism in higher eukaryotes in response to cytosolic double-stranded DNA (dsDNA). Since its initial discovery, detailed mechanisms delineating the dynamic subcellular localization of its different components and downstream signaling have been uncovered, leading to attempts to harness its proinflammatory properties for therapeutic benefit in cancer. Emerging evidence, however, indicates that a crucial primordial function of STING is to promote autophagy, and that downstream interferon (IFN) signaling emerged recently in its evolutionary history. Furthermore, studies suggest that this pathway is a crucial regulator of cellular metabolism that potentially couples inflammation to nutrient availability. We focus on the evolutionarily conserved functions of STING, and we discuss how a broader understanding of this pathway can help us to better appreciate its potential role in cancer and harness it for therapeutic benefit.
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http://dx.doi.org/10.1016/j.tibs.2020.12.010DOI Listing
January 2021

Metastasis and Immune Evasion from Extracellular cGAMP Hydrolysis.

Cancer Discov 2020 Dec 28. Epub 2020 Dec 28.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

Cytosolic DNA is characteristic of chromosomally unstable metastatic cancer cells, resulting in constitutive activation of the cGAS-STING innate immune pathway. How tumors co-opt inflammatory signaling while evading immune surveillance remains unknown. Here, we show that the ectonucleotidase ENPP1 promotes metastasis by selectively degrading extracellular cGAMP, an immune-stimulatory metabolite whose breakdown products include the immune suppressor adenosine. ENPP1 loss suppresses metastasis, restores tumor immune infiltration, and potentiates response to immune checkpoint blockade in a manner dependent on tumor cGAS and host STING. Conversely, overexpression of wild-type ENPP1, but not an enzymatically weakened mutant, promotes migration and metastasis, in part through the generation of extracellular adenosine, and renders otherwise sensitive tumors completely resistant to immunotherapy. In human cancers, ENPP1 expression correlates with reduced immune cell infiltration, increased metastasis, and resistance to anti-PD-1/PD-L1 treatment. Thus, cGAMP hydrolysis by ENPP1 enables chromosomally unstable tumors to transmute cGAS activation into an immune-suppressive pathway. SIGNIFICANCE: Chromosomal instability promotes metastasis by generating chronic tumor inflammation. ENPP1 facilitates metastasis and enables tumor cells to tolerate inflammation by hydrolyzing the immunotransmitter cGAMP, preventing its transfer from cancer cells to immune cells.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0387DOI Listing
December 2020

Re-awakening Innate Immune Signaling in Cancer: The Development of Highly Potent ENPP1 Inhibitors.

Cell Chem Biol 2020 11;27(11):1327-1328

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address:

Activation of innate immune signaling in the tumor microenvironment is central to a successful anti-tumor immune response, and it is in large part mediated by cytosolic double-stranded DNA sensing. Here, Carozza et al. (2020b) report potent and selective inhibitors of ENPP1, a negative regulator of innate immune signaling, which are shown to potentiate anti-tumor immune responses.
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http://dx.doi.org/10.1016/j.chembiol.2020.11.001DOI Listing
November 2020

Pervasive chromosomal instability and karyotype order in tumour evolution.

Nature 2020 11 2;587(7832):126-132. Epub 2020 Sep 2.

Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.

Chromosomal instability in cancer consists of dynamic changes to the number and structure of chromosomes. The resulting diversity in somatic copy number alterations (SCNAs) may provide the variation necessary for tumour evolution. Here we use multi-sample phasing and SCNA analysis of 1,421 samples from 394 tumours across 22 tumour types to show that continuous chromosomal instability results in pervasive SCNA heterogeneity. Parallel evolutionary events, which cause disruption in the same genes (such as BCL9, MCL1, ARNT (also known as HIF1B), TERT and MYC) within separate subclones, were present in 37% of tumours. Most recurrent losses probably occurred before whole-genome doubling, that was found as a clonal event in 49% of tumours. However, loss of heterozygosity at the human leukocyte antigen (HLA) locus and loss of chromosome 8p to a single haploid copy recurred at substantial subclonal frequencies, even in tumours with whole-genome doubling, indicating ongoing karyotype remodelling. Focal amplifications that affected chromosomes 1q21 (which encompasses BCL9, MCL1 and ARNT), 5p15.33 (TERT), 11q13.3 (CCND1), 19q12 (CCNE1) and 8q24.1 (MYC) were frequently subclonal yet appeared to be clonal within single samples. Analysis of an independent series of 1,024 metastatic samples revealed that 13 focal SCNAs were enriched in metastatic samples, including gains in chromosome 8q24.1 (encompassing MYC) in clear cell renal cell carcinoma and chromosome 11q13.3 (encompassing CCND1) in HER2 breast cancer. Chromosomal instability may enable the continuous selection of SCNAs, which are established as ordered events that often occur in parallel, throughout tumour evolution.
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http://dx.doi.org/10.1038/s41586-020-2698-6DOI Listing
November 2020

Morphology-Predicted Large-Scale Transition Number in Circulating Tumor Cells Identifies a Chromosomal Instability Biomarker Associated with Poor Outcome in Castration-Resistant Prostate Cancer.

Cancer Res 2020 11 19;80(22):4892-4903. Epub 2020 Aug 19.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Chromosomal instability (CIN) increases a tumor cell's ability to acquire chromosomal alterations, a mechanism by which tumor cells evolve, adapt, and resist therapeutics. We sought to develop a biomarker of CIN in circulating tumor cells (CTC) that are more likely to reflect the genetic diversity of patient's disease than a single-site biopsy and be assessed rapidly so as to inform treatment management decisions in real time. Large-scale transitions (LST) are genomic alterations defined as chromosomal breakages that generate chromosomal gains or losses of greater than or equal to10 Mb. Here we studied the relationship between the number of LST in an individual CTC determined by direct sequencing and morphologic features of the cells. This relationship was then used to develop a computer vision algorithm that utilizes CTC image features to predict the presence of a high (9 or more) versus low (8 or fewer) LST number in a single cell. As LSTs are a primary functional component of homologous recombination deficient cellular phenotypes, the image-based algorithm was studied prospectively on 10,240 CTCs in 367 blood samples obtained from 294 patients with progressing metastatic castration-resistant prostate cancer taken prior to starting a standard-of-care approved therapy. The resultant computer vision-based biomarker of CIN in CTCs in a pretreatment sample strongly associated with poor overall survival times in patients treated with androgen receptor signaling inhibitors and taxanes. SIGNIFICANCE: A rapidly assessable biomarker of chromosomal instability in CTC is associated with poor outcomes when detected in men with progressing mCRPC.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1216DOI Listing
November 2020

Limited Environmental Serine and Glycine Confer Brain Metastasis Sensitivity to PHGDH Inhibition.

Cancer Discov 2020 09 22;10(9):1352-1373. Epub 2020 Jun 22.

Department of Radiation Oncology, Perlmutter Cancer Center and NYU Langone Health, New York, New York.

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. , genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE: Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These findings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis..
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http://dx.doi.org/10.1158/2159-8290.CD-19-1228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483776PMC
September 2020

Breast Radiation Therapy Under COVID-19 Pandemic Resource Constraints-Approaches to Defer or Shorten Treatment From a Comprehensive Cancer Center in the United States.

Adv Radiat Oncol 2020 Jul-Aug;5(4):582-588. Epub 2020 Apr 1.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: Breast radiation therapy accounts for a significant proportion of patient volume in contemporary radiation oncology practice. In the setting of anticipated resource constraints and widespread community infection with SARS-CoV-2 during the COVID-19 pandemic, measures for balancing both infectious and oncologic risk among patients and providers must be carefully considered. Here, we present evidence-based guidelines for omitting or abbreviating breast cancer radiation therapy, where appropriate, in an effort to mitigate risk to patients and optimize resource utilization.

Methods And Materials: Multidisciplinary breast cancer experts at a high-volume comprehensive cancer center convened contingency planning meetings over the early days of the COVID-19 pandemic to review the relevant literature and establish recommendations for the application of hypofractionated and abbreviated breast radiation regimens.

Results: Substantial evidence exists to support omitting radiation among certain favorable risk subgroups of patients with breast cancer and for abbreviating or accelerating regimens among others. For those who require either whole-breast or postmastectomy radiation, with or without coverage of the regional lymph nodes, a growing body of literature supports various hypofractionated approaches that appear safe and effective.

Conclusions: In the setting of a public health emergency with the potential to strain critical healthcare resources and place patients at risk of infection, the parsimonious application of breast radiation therapy may alleviate a significant clinical burden without compromising long-term oncologic outcomes. The judicious and personalized use of immature study data may be warranted in the setting of a competing mortality risk from this widespread pandemic.
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http://dx.doi.org/10.1016/j.adro.2020.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118660PMC
April 2020

A CINful way to overcome addiction: how chromosomal instability enables cancer to overcome its oncogene addiction.

EMBO Mol Med 2020 03 18;12(3):e12017. Epub 2020 Feb 18.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Oncogene-addicted tumors present a valuable target for therapeutic intervention and an opportunity to achieve a wide therapeutic window. Nonetheless, resistance to targeted therapies is frequently observed and it arises through multiple mechanisms, including mutations in the target gene. Chromosomal instability, a defining feature of human cancer, has been linked to targeted therapy resistance, but the mechanism underlying this association is poorly understood. In the current issue of EMBO Molecular Medicine, Salgueiro et al show that chromosomal instability can lead to the generation of alternative oncogenic drivers, thereby providing the ability for cancer cells to overcome the oncogene withdrawal bottleneck. Importantly, this study shows that, by generating de novo genomic diversity, chromosomal instability serves as an adaptive response to therapeutic insult.
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http://dx.doi.org/10.15252/emmm.202012017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059011PMC
March 2020

Regenerative lineages and immune-mediated pruning in lung cancer metastasis.

Nat Med 2020 02 10;26(2):259-269. Epub 2020 Feb 10.

Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Developmental processes underlying normal tissue regeneration have been implicated in cancer, but the degree of their enactment during tumor progression and under the selective pressures of immune surveillance, remain unknown. Here we show that human primary lung adenocarcinomas are characterized by the emergence of regenerative cell types, typically seen in response to lung injury, and by striking infidelity among transcription factors specifying most alveolar and bronchial epithelial lineages. In contrast, metastases are enriched for key endoderm and lung-specifying transcription factors, SOX2 and SOX9, and recapitulate more primitive transcriptional programs spanning stem-like to regenerative pulmonary epithelial progenitor states. This developmental continuum mirrors the progressive stages of spontaneous outbreak from metastatic dormancy in a mouse model and exhibits SOX9-dependent resistance to natural killer cells. Loss of developmental stage-specific constraint in macrometastases triggered by natural killer cell depletion suggests a dynamic interplay between developmental plasticity and immune-mediated pruning during metastasis.
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http://dx.doi.org/10.1038/s41591-019-0750-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021003PMC
February 2020

The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer.

Cancer Discov 2020 01 18;10(1):26-39. Epub 2019 Dec 18.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York.

The recognition of DNA as an immune-stimulatory molecule is an evolutionarily conserved mechanism to initiate rapid innate immune responses against microbial pathogens. The cGAS-STING pathway was discovered as an important DNA-sensing machinery in innate immunity and viral defense. Recent advances have now expanded the roles of cGAS-STING to cancer. Highly aggressive, unstable tumors have evolved to co-opt this program to drive tumorigenic behaviors. In this review, we discuss the link between the cGAS-STING DNA-sensing pathway and antitumor immunity as well as cancer progression, genomic instability, the tumor microenvironment, and pharmacologic strategies for cancer therapy. SIGNIFICANCE: The cGAS-STING pathway is an evolutionarily conserved defense mechanism against viral infections. Given its role in activating immune surveillance, it has been assumed that this pathway primarily functions as a tumor suppressor. Yet, mounting evidence now suggests that depending on the context, cGAS-STING signaling can also have tumor and metastasis-promoting functions, and its chronic activation can paradoxically induce an immune-suppressive tumor microenvironment.
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http://dx.doi.org/10.1158/2159-8290.CD-19-0761DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7151642PMC
January 2020

Expanding the Role of STING in Cellular Homeostasis and Transformation.

Trends Cancer 2019 04 23;5(4):195-197. Epub 2019 Feb 23.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

The cytosolic DNA-sensing cGAS-STING pathway was originally characterized as a key innate immune mediator responsible for the induction of antiviral genes in response to foreign DNA species in the cytosol. Mounting evidence, however, points to a complex role for cGAS and STING in cancer. Two recent reports, by Ranoa et al. (Cancer Research, 2018;https://doi.org/10.1158/0008-5472.CAN-18-1972) and Nassour et al. (Nature 2019;565:659-663), dissect the function of this pathway during the early steps of cellular transformation and shed light on the complexity and context-dependence of cGAS-STING signaling in cancer.
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http://dx.doi.org/10.1016/j.trecan.2019.02.001DOI Listing
April 2019

A Markov chain for numerical chromosomal instability in clonally expanding populations.

PLoS Comput Biol 2018 09 11;14(9):e1006447. Epub 2018 Sep 11.

Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.

Cancer cells frequently undergo chromosome missegregation events during mitosis, whereby the copies of a given chromosome are not distributed evenly among the two daughter cells, thus creating cells with heterogeneous karyotypes. A stochastic model tracing cellular karyotypes derived from clonal populations over hundreds of generations was recently developed and experimentally validated, and it was capable of predicting favorable karyotypes frequently observed in cancer. Here, we construct and study a Markov chain that precisely describes karyotypic evolution during clonally expanding cancer cell populations. The Markov chain allows us to directly predict the distribution of karyotypes and the expected size of the tumor after many cell divisions without resorting to computationally expensive simulations. We determine the limiting karyotype distribution of an evolving tumor population, and quantify its dependency on several key parameters including the initial karyotype of the founder cell, the rate of whole chromosome missegregation, and chromosome-specific cell viability. Using this model, we confirm the existence of an optimal rate of chromosome missegregation probabilities that maximizes karyotypic heterogeneity, while minimizing the occurrence of nullisomy. Interestingly, karyotypic heterogeneity is significantly more dependent on chromosome missegregation probabilities rather than the number of cell divisions, so that maximal heterogeneity can be reached rapidly (within a few hundred generations of cell division) at chromosome missegregation rates commonly observed in cancer cell lines. Conversely, at low missegregation rates, heterogeneity is constrained even after thousands of cell division events. This leads us to conclude that chromosome copy number heterogeneity is primarily constrained by chromosome missegregation rates and the risk for nullisomy and less so by the age of the tumor. This model enables direct integration of karyotype information into existing models of tumor evolution based on somatic mutations.
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http://dx.doi.org/10.1371/journal.pcbi.1006447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6150543PMC
September 2018

The Multifaceted Role of Chromosomal Instability in Cancer and Its Microenvironment.

Cell 2018 09;174(6):1347-1360

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.

Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in chromosome segregation during mitosis, leading to structural and numerical chromosomal abnormalities. In addition to generating genomic heterogeneity that acts as a substrate for natural selection, CIN promotes inflammatory signaling by introducing double-stranded DNA into the cytosol, engaging the cGAS-STING anti-viral pathway. These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.
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http://dx.doi.org/10.1016/j.cell.2018.08.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6136429PMC
September 2018

Insights into clonal haematopoiesis from 8,342 mosaic chromosomal alterations.

Nature 2018 07 11;559(7714):350-355. Epub 2018 Jul 11.

Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.

The selective pressures that shape clonal evolution in healthy individuals are largely unknown. Here we investigate 8,342 mosaic chromosomal alterations, from 50 kb to 249 Mb long, that we uncovered in blood-derived DNA from 151,202 UK Biobank participants using phase-based computational techniques (estimated false discovery rate, 6-9%). We found six loci at which inherited variants associated strongly with the acquisition of deletions or loss of heterozygosity in cis. At three such loci (MPL, TM2D3-TARSL2, and FRA10B), we identified a likely causal variant that acted with high penetrance (5-50%). Inherited alleles at one locus appeared to affect the probability of somatic mutation, and at three other loci to be objects of positive or negative clonal selection. Several specific mosaic chromosomal alterations were strongly associated with future haematological malignancies. Our results reveal a multitude of paths towards clonal expansions with a wide range of effects on human health.
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http://dx.doi.org/10.1038/s41586-018-0321-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054542PMC
July 2018

SnapShot: CGAS-STING Signaling.

Cell 2018 03;173(1):276-276.e1

Department of Radiation Oncology, Weill Cornell Medical College, New York, NY, USA; Sandra and Edward Meyer Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.

CGAS responds to cytosolic DNA by initiating a STING-dependent response that ultimately engages innate immune effectors to ensure the preservation of organismal homeostasis.
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http://dx.doi.org/10.1016/j.cell.2018.03.015DOI Listing
March 2018

Chromosomal instability drives metastasis through a cytosolic DNA response.

Nature 2018 01 17;553(7689):467-472. Epub 2018 Jan 17.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065, USA.

Chromosomal instability is a hallmark of cancer that results from ongoing errors in chromosome segregation during mitosis. Although chromosomal instability is a major driver of tumour evolution, its role in metastasis has not been established. Here we show that chromosomal instability promotes metastasis by sustaining a tumour cell-autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signalling. Genetic suppression of chromosomal instability markedly delays metastasis even in highly aneuploid tumour models, whereas continuous chromosome segregation errors promote cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumour cells co-opt chronic activation of innate immune pathways to spread to distant organs.
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http://dx.doi.org/10.1038/nature25432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5785464PMC
January 2018

Cancer Evolution: No Room for Negative Selection.

Cell 2017 11;171(5):987-989

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Division of Hematology and Medical Oncology, Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA; New York Genome Center, New York, NY 10013, USA. Electronic address:

In this issue of Cell, Martincorena et al. and Campbell et al. interrogated the selection dynamics during tumor evolution using large-scale genomics datasets. They found that somatic mutations in cancer are largely neutral, highlighting a near-complete absence of negative selection. Neutral evolution enables tolerance of hypermutation, which defines a surprisingly large fraction of adult cancer.
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http://dx.doi.org/10.1016/j.cell.2017.10.039DOI Listing
November 2017

Mitotic DNA Damage Response: At the Crossroads of Structural and Numerical Cancer Chromosome Instabilities.

Trends Cancer 2017 03 28;3(3):225-234. Epub 2017 Feb 28.

Institute of Molecular Oncology, Section for Cellular Oncology, Goettingen Center for Molecular Biosciences (GZMB) and University Medical Center, University of Göttingen, D-37077 Goettingen, Germany.

DNA double-strand breaks (DSBs) prevent cells from entering mitosis allowing cells to repair their genomic damage. Little is known about the response to DSBs once cells have already committed to mitosis. Here, we review the genome-protective role of the mitotic DNA damage response (DDR) and evidence suggesting that its untimely activation induces chromosome segregation errors and paradoxically undermines genomic integrity. In contrast to normal cells, cancer cells coopt this pathway to propagate structural and numerical chromosomal instabilities. Cells derived from genomically unstable tumors exhibit evidence for a partially activated DDR during mitosis, which leads to ongoing chromosome segregation errors. Thus, a thorough understanding of the consequences of mitotic DNA damage is key to our ability to devise novel anticancer therapeutic strategies.
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http://dx.doi.org/10.1016/j.trecan.2017.02.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518619PMC
March 2017

Chromosomal Instability as a Driver of Tumor Heterogeneity and Evolution.

Cold Spring Harb Perspect Med 2017 Jun 1;7(6). Epub 2017 Jun 1.

Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, New York 10065.

Large-scale, massively parallel sequencing of human cancer samples has revealed tremendous genetic heterogeneity within individual tumors. Indeed, tumors are composed of an admixture of diverse subpopulations-subclones-that vary in space and time. Here, we discuss a principal driver of clonal diversification in cancer known as chromosomal instability (CIN), which complements other modes of genetic diversification creating the multilayered genomic instability often seen in human cancer. Cancer cells have evolved to fine-tune chromosome missegregation rates to balance the acquisition of heterogeneity while preserving favorable genotypes, a dependence that can be exploited for a therapeutic benefit. We discuss how whole-genome doubling events accelerate clonal evolution in a subset of tumors by providing a viable path toward favorable near-triploid karyotypes and present evidence for CIN-induced clonal speciation that can overcome the dependence on truncal initiating events.
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http://dx.doi.org/10.1101/cshperspect.a029611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5453382PMC
June 2017

Dynamics of Tumor Heterogeneity Derived from Clonal Karyotypic Evolution.

Cell Rep 2015 Aug 23;12(5):809-20. Epub 2015 Jul 23.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

Numerical chromosomal instability is a ubiquitous feature of human neoplasms. Due to experimental limitations, fundamental characteristics of karyotypic changes in cancer are poorly understood. Using an experimentally inspired stochastic model, based on the potency and chromosomal distribution of oncogenes and tumor suppressor genes, we show that cancer cells have evolved to exist within a narrow range of chromosome missegregation rates that optimizes phenotypic heterogeneity and clonal survival. Departure from this range reduces clonal fitness and limits subclonal diversity. Mapping of the aneuploid fitness landscape reveals a highly favorable, commonly observed, near-triploid state onto which evolving diploid- and tetraploid-derived populations spontaneously converge, albeit at a much lower fitness cost for the latter. Finally, by analyzing 1,368 chromosomal translocation events in five human cancers, we find that karyotypic evolution also shapes chromosomal translocation patterns by selecting for more oncogenic derivative chromosomes. Thus, chromosomal instability can generate the heterogeneity required for Darwinian tumor evolution.
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http://dx.doi.org/10.1016/j.celrep.2015.06.065DOI Listing
August 2015

Numerical chromosomal instability mediates susceptibility to radiation treatment.

Nat Commun 2015 Jan 21;6:5990. Epub 2015 Jan 21.

1] Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA [2] Norris-Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire 03756, USA.

The exquisite sensitivity of mitotic cancer cells to ionizing radiation (IR) underlies an important rationale for the widely used fractionated radiation therapy. However, the mechanism for this cell cycle-dependent vulnerability is unknown. Here we show that treatment with IR leads to mitotic chromosome segregation errors in vivo and long-lasting aneuploidy in tumour-derived cell lines. These mitotic errors generate an abundance of micronuclei that predispose chromosomes to subsequent catastrophic pulverization thereby independently amplifying radiation-induced genome damage. Experimentally suppressing whole-chromosome missegregation reduces downstream chromosomal defects and significantly increases the viability of irradiated mitotic cells. Further, orthotopically transplanted human glioblastoma tumours in which chromosome missegregation rates have been reduced are rendered markedly more resistant to IR, exhibiting diminished markers of cell death in response to treatment. This work identifies a novel mitotic pathway for radiation-induced genome damage, which occurs outside of the primary nucleus and augments chromosomal breaks. This relationship between radiation treatment and whole-chromosome missegregation can be exploited to modulate therapeutic response in a clinically relevant manner.
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http://dx.doi.org/10.1038/ncomms6990DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516720PMC
January 2015

Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence.

N Engl J Med 2014 Dec 26;371(26):2477-87. Epub 2014 Nov 26.

The authors' affiliations are listed in the Appendix.

Background: Cancers arise from multiple acquired mutations, which presumably occur over many years. Early stages in cancer development might be present years before cancers become clinically apparent.

Methods: We analyzed data from whole-exome sequencing of DNA in peripheral-blood cells from 12,380 persons, unselected for cancer or hematologic phenotypes. We identified somatic mutations on the basis of unusual allelic fractions. We used data from Swedish national patient registers to follow health outcomes for 2 to 7 years after DNA sampling.

Results: Clonal hematopoiesis with somatic mutations was observed in 10% of persons older than 65 years of age but in only 1% of those younger than 50 years of age. Detectable clonal expansions most frequently involved somatic mutations in three genes (DNMT3A, ASXL1, and TET2) that have previously been implicated in hematologic cancers. Clonal hematopoiesis was a strong risk factor for subsequent hematologic cancer (hazard ratio, 12.9; 95% confidence interval, 5.8 to 28.7). Approximately 42% of hematologic cancers in this cohort arose in persons who had clonality at the time of DNA sampling, more than 6 months before a first diagnosis of cancer. Analysis of bone marrow-biopsy specimens obtained from two patients at the time of diagnosis of acute myeloid leukemia revealed that their cancers arose from the earlier clones.

Conclusions: Clonal hematopoiesis with somatic mutations is readily detected by means of DNA sequencing, is increasingly common as people age, and is associated with increased risks of hematologic cancer and death. A subset of the genes that are mutated in patients with myeloid cancers is frequently mutated in apparently healthy persons; these mutations may represent characteristic early events in the development of hematologic cancers. (Funded by the National Human Genome Research Institute and others.).
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http://dx.doi.org/10.1056/NEJMoa1409405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4290021PMC
December 2014

DNA-damage response during mitosis induces whole-chromosome missegregation.

Cancer Discov 2014 Nov 8;4(11):1281-9. Epub 2014 Aug 8.

Department of Biochemistry, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire. Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.

Unlabelled: Many cancers display both structural (s-CIN) and numerical (w-CIN) chromosomal instabilities. Defective chromosome segregation during mitosis has been shown to cause DNA damage that induces structural rearrangements of chromosomes (s-CIN). In contrast, whether DNA damage can disrupt mitotic processes to generate whole chromosomal instability (w-CIN) is unknown. Here, we show that activation of the DNA-damage response (DDR) during mitosis selectively stabilizes kinetochore-microtubule (k-MT) attachments to chromosomes through Aurora-A and PLK1 kinases, thereby increasing the frequency of lagging chromosomes during anaphase. Inhibition of DDR proteins, ATM or CHK2, abolishes the effect of DNA damage on k-MTs and chromosome segregation, whereas activation of the DDR in the absence of DNA damage is sufficient to induce chromosome segregation errors. Finally, inhibiting the DDR during mitosis in cancer cells with persistent DNA damage suppresses inherent chromosome segregation defects. Thus, the DDR during mitosis inappropriately stabilizes k-MTs, creating a link between s-CIN and w-CIN.

Significance: The genome-protective role of the DDR depends on its ability to delay cell division until damaged DNA can be fully repaired. Here, we show that when DNA damage is induced during mitosis, the DDR unexpectedly induces errors in the segregation of entire chromosomes, thus linking structural and numerical chromosomal instabilities.
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http://dx.doi.org/10.1158/2159-8290.CD-14-0403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221427PMC
November 2014

Chromosomal instability, aneuploidy, and cancer.

Front Oncol 2014 19;4:161. Epub 2014 Jun 19.

Cancer Research UK London Research Institute , London , UK ; University College London Cancer Institute , London , UK.

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http://dx.doi.org/10.3389/fonc.2014.00161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062911PMC
July 2014

Chromosomal instability portends superior response of rectal adenocarcinoma to chemoradiation therapy.

Cancer 2014 Jun 6;120(11):1733-42. Epub 2014 Mar 6.

Section of Radiation Oncology, Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Dartmouth College, Lebanon, New Hampshire.

Background: Persistent chromosome segregation errors represent a conspicuous feature of human neoplasms. It is widely accepted that this chromosomal instability is associated with poor prognosis; however, its effect on therapeutic response is a matter of conjecture.

Methods: Here, the role of chromosome segregation errors in the response of patients with rectal adenocarcinoma to chemoradiation therapy (CRT) was examined. Pretreatment samples from 62 patients were surveyed for evidence of chromosome mis-segregation and mis-segregation frequency was correlated to the pathological response to CRT as determined by the tumor regression grade after surgical resection of irradiated tumors.

Results: Surprisingly, it was found that errors in chromosome segregation predicted enhanced pathological response of rectal adenocarcinoma to CRT (odds ratio, 3.9; P = .02). Furthermore, tumor response inversely correlated with the frequency of cells that exhibited segregation errors during anaphase (correlation coefficient, 0.94; P < .05). Strikingly, elevated chromosome mis-segregation combined with decreased levels of the DNA damage repair protein Mre11 portended a markedly enhanced response (odds ratio, 54.0; P = .008).

Conclusions: The results of the current study demonstrate that chromosomal instability is a favorable predictor of response to CRT in patients with locally invasive rectal adenocarcinoma. Therefore, the authors propose that downstream structural damage to chromosomes resulting from segregation errors potentiates the effect of DNA-damaging therapies and synergizes with deficiencies in the DNA repair machinery. This work identifies a novel mechanistic marker that foretells treatment response to CRT and suggests that concomitant targeting of whole-chromosome segregation and DNA repair may constitute an effective therapeutic strategy.
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http://dx.doi.org/10.1002/cncr.28656DOI Listing
June 2014

The mitotic origin of chromosomal instability.

Curr Biol 2014 Feb;24(4):R148-9

Department of Biological Sciences, Virginia Tech, Blacksburg, VA 24061, USA; Virginia Bioinformatics Institute, Virginia Tech, Blacksburg, VA 24061, USA. Electronic address:

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http://dx.doi.org/10.1016/j.cub.2014.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3970164PMC
February 2014

A predictive model of complications after spine surgery: the National Surgical Quality Improvement Program (NSQIP) 2005-2010.

Spine J 2014 Jul 4;14(7):1247-55. Epub 2013 Oct 4.

Department of Neurosurgery, Portsmouth Hospital, 333 Borthwick Ave., Portsmouth, NH 03801, USA.

Background Context: There is increasing scrutiny by several regulatory bodies regarding the complications of spine surgery. Precise delineation of the risks contributing to those complications remains a topic of debate.

Purpose: We attempted to create a predictive model of complications in patients undergoing spine surgery.

Study Design/setting: Retrospective cohort study.

Patient Sample: A total of 13,660 patients registered in the American College of Surgeons National Quality Improvement Project (NSQIP) database.

Outcome Measures: Thirty-day postoperative risks of stroke, myocardial infarction, death, infection, urinary tract infection (UTI), deep vein thrombosis (DVT), pulmonary embolism (PE), and return to the operating room.

Methods: We performed a retrospective cohort study involving patients who underwent spine surgery between 2005 and 2010 and were registered in NSQIP. A model for outcome prediction based on individual patient characteristics was developed.

Results: Of the 13,660 patients, 2,719 underwent anterior approaches (19.9%), 565 corpectomies (4.1%), and 1,757 fusions (12.9%). The respective 30-day postoperative risks were 0.05% for stroke, 0.2% for MI, 0.25% for death, 0.3% for infection, 1.37% for UTI, 0.6% for DVT, 0.29% for PE, and 3.15% for return to the operating room. Multivariate analysis demonstrated that increasing age, more extensive operations (fusion, corpectomy), medical deconditioning (weight loss, dialysis, peripheral vascular disease, coronary artery disease, chronic obstructive pulmonary disease, diabetes), increasing body mass index, non-independent mobilization (preoperative neurologic deficit), and bleeding disorders were independently associated with a more than 3 days' length of stay. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated by the area under the receiver operating characteristic curve, which was 0.95, 0.82, 0.87, 0.75, 0.74, 0.78, 0.76, 0.74, and 0.65 for postoperative risk of stroke, myocardial infarction, death, infection, DVT, PE, UTI, length of stay of 3 days or longer, and return to the operating room, respectively.

Conclusions: Our model can provide individualized estimates of the risks of postoperative complications based on preoperative conditions, and can potentially be used as an adjunct in decision-making for spine surgery.
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http://dx.doi.org/10.1016/j.spinee.2013.08.009DOI Listing
July 2014

Outcome prediction in intracranial tumor surgery: the National Surgical Quality Improvement Program 2005-2010.

J Neurooncol 2013 May 24;113(1):57-64. Epub 2013 Feb 24.

Section of Neurosurgery, Dartmouth-Hitchcock Medical Center, One Medical Center Dr, Lebanon, NH 03756, USA.

Accurate knowledge of individualized risks is crucial for decision-making in the surgical management of patients with brain tumors. Precise delineation of those risks remains a topic of debate. We attempted to create a predictive model of outcomes in patients undergoing craniotomies for tumor resection (CTR). We performed a retrospective cohort study involving patients who underwent CTR from 2005 to 2010 and were registered in the American College of Surgeons National Quality Improvement Project database. A model for outcome prediction based on individual patient characteristics was developed. Of the 1,834 patients, 457 had meningiomas (24.9 %) and 1377 had non-meningioma tumors (75.1 %). The respective 30-day postoperative risks were 2.1 % for stroke, 1.3 % for MI, 2.7 % for death, 2.4 % for deep surgical site infection, and 6.6 % for return to the OR. Multivariate analysis demonstrated that pre-operative tumor-related neurologic deficit, stroke, altered mental status, and weight loss, were independently associated with most outcomes, including post-operative MI, death, and deep surgical site infection. An additive effect of the variables on the risk of all outcomes was observed. A validated model for outcome prediction based on individual patient characteristics was developed. The accuracy of the model was estimated by the area under the receiver operating characteristic curve, which was 0.687, 0.929, 0.749, 0.746, and 0.679 for postoperative risk of stroke, MI, death, infection, and return to the OR, respectively. Our model can provide individualized estimates of the risks of post-operative complications based on pre-operative conditions, and can potentially be utilized as an adjunct in the decision-making for surgical intervention in brain tumor patients.
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http://dx.doi.org/10.1007/s11060-013-1089-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617728PMC
May 2013

A risk factor-based predictive model of outcomes in carotid endarterectomy: the National Surgical Quality Improvement Program 2005-2010.

Stroke 2013 Apr 14;44(4):1085-1090. Epub 2013 Feb 14.

Section of Neurosurgery (K.B., A.D.), Department of Medicine (T.A.M.), and Section of Vascular Surgery (P.G.), Dartmouth-Hitchcock Medical Center, Lebanon, NH; Geisel School of Medicine at Dartmouth (S.F.B.), Hanover, NH; and Section of Vascular Surgery, State University of New York at Stony Brook, Stony Brook, NY (N.L.).

Background And Purpose: Accurate knowledge of individualized risks and benefits is crucial to the surgical management of patients undergoing carotid endarterectomy (CEA). Although large randomized trials have determined specific cutoffs for the degree of stenosis, precise delineation of patient-level risks remains a topic of debate, especially in real world practice. We attempted to create a risk factor-based predictive model of outcomes in CEA.

Methods: We performed a retrospective cohort study involving patients who underwent CEAs from 2005 to 2010 and were registered in the American College of Surgeons National Quality Improvement Project database.

Results: Of the 35 698 patients, 20 015 were asymptomatic (56.1%) and 15 683 were symptomatic (43.9%). These patients demonstrated a 1.64% risk of stroke, 0.69% risk of myocardial infarction, and 0.75% risk of death within 30 days after CEA. Multivariate analysis demonstrated that increasing age, male sex, history of chronic obstructive pulmonary disease, myocardial infarction, angina, congestive heart failure, peripheral vascular disease, previous stroke or transient ischemic attack, and dialysis were independent risk factors associated with an increased risk of the combined outcome of postoperative stroke, myocardial infarction, or death. A validated model for outcome prediction based on individual patient characteristics was developed. There was a steep effect of age on the risk of myocardial infarction and death.

Conclusions: This national study confirms that that risks of CEA vary dramatically based on patient-level characteristics. Because of limited discrimination, it cannot be used for individual patient risk assessment. However, it can be used as a baseline for improvement and development of more accurate predictive models based on other databases or prospective studies.
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http://dx.doi.org/10.1161/STROKEAHA.111.674358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4279219PMC
April 2013

Chromosomal instability and cancer: a complex relationship with therapeutic potential.

J Clin Invest 2012 Apr 2;122(4):1138-43. Epub 2012 Apr 2.

Department of Biochemistry and Norris Cotton Cancer Center, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

Chromosomal instability (CIN) is a hallmark of human neoplasms. Despite its widespread prevalence, knowledge of the mechanisms and contributions of CIN in cancer has been elusive. It is now evident that the role of CIN in tumor initiation and growth is more complex than previously thought. Furthermore, distinguishing CIN, which consists of elevated rates of chromosome missegregation, from aneuploidy, which is a state of abnormal chromosome number, is crucial to understanding their respective contributions in cancer. Collectively, experimental evidence suggests that CIN enables tumor adaptation by allowing tumors to constantly sample the aneuploid fitness landscape. This complex relationship, together with the potential to pharmacologically influence chromosome missegregation frequencies in cancer cells, offers previously unrecognized means to limit tumor growth and its response to therapy.
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http://dx.doi.org/10.1172/JCI59954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314464PMC
April 2012