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Cell Sep 2018Chromosomal instability (CIN) is a hallmark of human cancer, and it is associated with poor prognosis, metastasis, and therapeutic resistance. CIN results from errors in... (Review)
Review
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.
Topics: Aneuploidy; Chromosomal Instability; Humans; Immunity, Innate; Interferon Type I; Membrane Proteins; Neoplasms; Nucleotidyltransferases; Signal Transduction; Tumor Microenvironment
PubMed: 30193109
DOI: 10.1016/j.cell.2018.08.027 -
Nature Jun 2022Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA. The broad genomic complexity caused by CIN is a...
Chromosomal instability (CIN) results in the accumulation of large-scale losses, gains and rearrangements of DNA. The broad genomic complexity caused by CIN is a hallmark of cancer; however, there is no systematic framework to measure different types of CIN and their effect on clinical phenotypes pan-cancer. Here we evaluate the extent, diversity and origin of CIN across 7,880 tumours representing 33 cancer types. We present a compendium of 17 copy number signatures that characterize specific types of CIN, with putative aetiologies supported by multiple independent data sources. The signatures predict drug response and identify new drug targets. Our framework refines the understanding of impaired homologous recombination, which is one of the most therapeutically targetable types of CIN. Our results illuminate a fundamental structure underlying genomic complexity in human cancers and provide a resource to guide future CIN research.
Topics: Chromosomal Instability; Homologous Recombination; Humans; Molecular Targeted Therapy; Neoplasms
PubMed: 35705807
DOI: 10.1038/s41586-022-04789-9 -
Developmental Cell Sep 2021Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of...
Mitotic errors lead to aneuploidy, a condition of karyotype imbalance, frequently found in cancer cells. Alterations in chromosome copy number induce a wide variety of cellular stresses, including genome instability. Here, we show that cancer cells might exploit aneuploidy-induced genome instability and the resulting gene copy-number changes to survive under conditions of selective pressure, such as chemotherapy. Resistance to chemotherapeutic drugs was dictated by the acquisition of recurrent karyotypes, indicating that gene dosage might play a role in driving chemoresistance. Thus, our study establishes a causal link between aneuploidy-driven changes in gene copy number and chemoresistance and might explain why some chemotherapies fail to succeed.
Topics: Aneuploidy; Chromosomal Instability; Drug Resistance; Drug Therapy; Gene Dosage; Genomic Instability; Humans; Karyotype
PubMed: 34352223
DOI: 10.1016/j.devcel.2021.07.006 -
Science Translational Medicine Sep 2021Paclitaxel (Taxol) is a cornerstone of cancer treatment. However, its mechanism of cytotoxicity is incompletely understood and not all patients benefit from treatment....
Paclitaxel (Taxol) is a cornerstone of cancer treatment. However, its mechanism of cytotoxicity is incompletely understood and not all patients benefit from treatment. We show that patients with breast cancer did not accumulate sufficient intratumoral paclitaxel to induce mitotic arrest in tumor cells. Instead, clinically relevant concentrations induced multipolar mitotic spindle formation. However, the extent of early multipolarity did not predict patient response. Whereas multipolar divisions frequently led to cell death, multipolar spindles focused into bipolar spindles before division at variable frequency, and maintaining multipolarity throughout mitosis was critical to induce the high rates of chromosomal instability necessary for paclitaxel to elicit cell death. Increasing multipolar divisions in paclitaxel resulted in improved cytotoxicity. Conversely, decreasing paclitaxel-induced multipolar divisions reduced paclitaxel efficacy. Moreover, we found that preexisting chromosomal instability sensitized breast cancer cells to paclitaxel. Both genetic and pharmacological methods of inducing chromosomal instability were sufficient to increase paclitaxel efficacy. In patients, the amount of pretreatment chromosomal instability directly correlated with taxane response in metastatic breast cancer such that patients with a higher rate of preexisting chromosomal instability showed improved response to taxanes. Together, these results support the use of baseline rates of chromosomal instability as a predictive biomarker for paclitaxel response. Furthermore, they suggest that agents that increase chromosomal instability or maintain multipolar spindles throughout mitosis will improve the clinical utility of paclitaxel.
Topics: Breast Neoplasms; Chromosomal Instability; Female; Humans; Paclitaxel
PubMed: 34516829
DOI: 10.1126/scitranslmed.abd4811 -
Developmental Cell Sep 2021Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could...
Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.
Topics: Aneuploidy; Cell Line, Tumor; Chromosomal Instability; Drug Resistance; Environment; Humans; Neoplasms; Treatment Outcome
PubMed: 34352222
DOI: 10.1016/j.devcel.2021.07.009 -
Cell Dec 2023Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data...
Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.
Topics: Humans; Chromosomal Instability; Colorectal Neoplasms; Gene Expression Profiling; Microsatellite Instability; p21-Activated Kinases; Tumor Microenvironment; Phylogeny; Mutation; Disease Progression; Prognosis
PubMed: 38065082
DOI: 10.1016/j.cell.2023.11.006 -
Nature Apr 2022Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of...
Diploid and stable karyotypes are associated with health and fitness in animals. By contrast, whole-genome duplications-doublings of the entire complement of chromosomes-are linked to genetic instability and frequently found in human cancers. It has been established that whole-genome duplications fuel chromosome instability through abnormal mitosis; however, the immediate consequences of tetraploidy in the first interphase are not known. This is a key question because single whole-genome duplication events such as cytokinesis failure can promote tumorigenesis. Here we find that human cells undergo high rates of DNA damage during DNA replication in the first S phase following induction of tetraploidy. Using DNA combing and single-cell sequencing, we show that DNA replication dynamics is perturbed, generating under- and over-replicated regions. Mechanistically, we find that these defects result from a shortage of proteins during the G1/S transition, which impairs the fidelity of DNA replication. This work shows that within a single interphase, unscheduled tetraploid cells can acquire highly abnormal karyotypes. These findings provide an explanation for the genetic instability landscape that favours tumorigenesis after tetraploidization.
Topics: Chromosomal Instability; DNA Damage; DNA Replication; Gene Duplication; Humans; Karyotype; Mitosis; S Phase; Tetraploidy
PubMed: 35355016
DOI: 10.1038/s41586-022-04578-4 -
Acta Neuropathologica Communications Aug 2022Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a... (Review)
Review
Chromosomal instability (CIN) is a fundamental property of cancer and a key underlying mechanism of tumorigenesis and malignant progression, and has been documented in a wide variety of cancers, including colorectal carcinoma with mutations in genes such as APC. Recent reports have demonstrated that CIN, driven in part by mutations in genes maintaining overall genomic stability, is found in subsets of adult-type diffusely infiltrating gliomas of all histologic and molecular grades, with resulting elevated overall copy number burden, chromothripsis, and poor clinical outcome. Still, relatively few studies have examined the effect of this process, due in part to the difficulty of routinely measuring CIN clinically. Herein, we review the underlying mechanisms of CIN, the relationship between chromosomal instability and malignancy, the prognostic significance and treatment potential in various cancers, systemic disease, and more specifically, in diffusely infiltrating glioma subtypes. While still in the early stages of discovery compared to other solid tumor types in which CIN is a known driver of malignancy, the presence of CIN as an early factor in gliomas may in part explain the ability of these tumors to develop resistance to standard therapy, while also providing a potential molecular target for future therapies.
Topics: Adult; Chromosomal Instability; Chromothripsis; Glioma; Humans; Mutation; Prognosis
PubMed: 35978439
DOI: 10.1186/s40478-022-01420-w -
Genes Feb 2020Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the... (Review)
Review
Since the discovery of the DNA double helix, there has been a fascination in understanding the molecular mechanisms and cellular processes that account for: (i) the transmission of genetic information from one generation to the next and (ii) the remarkable stability of the genome. Nucleic acid biologists have endeavored to unravel the mysteries of DNA not only to understand the processes of DNA replication, repair, recombination, and transcription but to also characterize the underlying basis of genetic diseases characterized by chromosomal instability. Perhaps unexpectedly at first, DNA helicases have arisen as a key class of enzymes to study in this latter capacity. From the first discovery of ATP-dependent DNA unwinding enzymes in the mid 1970's to the burgeoning of helicase-dependent pathways found to be prevalent in all kingdoms of life, the story of scientific discovery in helicase research is rich and informative. Over four decades after their discovery, we take this opportunity to provide a history of DNA helicases. No doubt, many chapters are left to be written. Nonetheless, at this juncture we are privileged to share our perspective on the DNA helicase field - where it has been, its current state, and where it is headed.
Topics: Adenosine Triphosphate; Chromosomal Instability; DNA; DNA Helicases; DNA Repair; DNA Replication; Humans; Nucleic Acids
PubMed: 32120966
DOI: 10.3390/genes11030255 -
Cancer Research Aug 2019Chromosomal instability (CIN) is one of the major forms of genomic instability in various human cancers and is recognized as a common hallmark of tumorigenesis and... (Review)
Review
Chromosomal instability (CIN) is one of the major forms of genomic instability in various human cancers and is recognized as a common hallmark of tumorigenesis and heterogeneity. However, some malignant tumors show a paucity of chromosomal alterations, suggesting that tumor progression and evolution can occur in the absence of CIN. It is unclear whether CIN is stable between precursor lesions, primary tumor, and metastases or if it evolves during these steps. In this review, we describe the influence of CIN on the various steps in tumor initiation and development. Given the recognized significant effects of CIN in cancer, CIN-targeted therapeutics could have a major impact on improving clinical outcomes.
Topics: Aneuploidy; Chromosomal Instability; Chromosome Segregation; Chromothripsis; Drug Resistance, Neoplasm; Female; Humans; Male; Neoplasms; Precancerous Conditions
PubMed: 31350294
DOI: 10.1158/0008-5472.CAN-18-3235