Authors: Ruben M Drews, Barbara Hernando, Maxime Tarabichi...

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

Authors: Marica Rosaria Ippolito, Valentino Martis, Sara Martin...

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

Review

Authors: Rendy Hosea, Sharon Hillary, Sumera Naqvi...

Chromosomal instability (CIN) is a hallmark of cancer and is associated with tumor cell malignancy. CIN triggers a chain reaction in cells leading to chromosomal abnormalities, including deviations from the normal chromosome number or structural changes in chromosomes. CIN arises from errors in DNA replication and chromosome segregation during cell division, leading to the formation of cells with abnormal number and/or structure of chromosomes. Errors in DNA replication result from abnormal replication licensing as well as replication stress, such as double-strand breaks and stalled replication forks; meanwhile, errors in chromosome segregation stem from defects in chromosome segregation machinery, including centrosome amplification, erroneous microtubule-kinetochore attachments, spindle assembly checkpoint, or defective sister chromatids cohesion. In normal cells, CIN is deleterious and is associated with DNA damage, proteotoxic stress, metabolic alteration, cell cycle arrest, and senescence. Paradoxically, despite these negative consequences, CIN is one of the hallmarks of cancer found in over 90% of solid tumors and in blood cancers. Furthermore, CIN could endow tumors with enhanced adaptation capabilities due to increased intratumor heterogeneity, thereby facilitating adaptive resistance to therapies; however, excessive CIN could induce tumor cells death, leading to the "just-right" model for CIN in tumors. Elucidating the complex nature of CIN is crucial for understanding the dynamics of tumorigenesis and for developing effective anti-tumor treatments. This review provides an overview of causes and consequences of CIN, as well as the paradox of CIN, a phenomenon that continues to perplex researchers. Finally, this review explores the potential of CIN-based anti-tumor therapy.

Topics: Humans; Chromosomal Instability; Kinetochores; Cell Line, Tumor; Centrosome; Microtubules; Neoplasms

PubMed: 38553459
DOI: 10.1038/s41392-024-01767-7

Authors: Cody N Heiser, Alan J Simmons, Frank Revetta...

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

Review

Authors: Melody Di Bona, Samuel F Bakhoum

UNLABELLED

Chromosome-containing micronuclei are a feature of human cancer. Micronuclei arise from chromosome mis-segregation and characterize tumors with elevated rates of chromosomal instability. Although their association with cancer has been long recognized, only recently have we broadened our understanding of the mechanisms that govern micronuclei formation and their role in tumor progression. In this review, we provide a brief historical account of micronuclei, depict the mechanisms underpinning their creation, and illuminate their capacity to propel tumor evolution through genetic, epigenetic, and transcriptional transformations. We also posit the prospect of leveraging micronuclei as biomarkers and therapeutic targets in chromosomally unstable cancers.

SIGNIFICANCE

Micronuclei in chromosomally unstable cancer cells serve as pivotal catalysts for cancer progression, instigating transformative genomic, epigenetic, and transcriptional alterations. This comprehensive review not only synthesizes our present comprehension but also outlines a framework for translating this knowledge into pioneering biomarkers and therapeutics, thereby illuminating novel paths for personalized cancer management.

Topics: Humans; Neoplasms; Chromosomal Instability; Chromosome Segregation; Biomarkers

PubMed: 38197599
DOI: 10.1158/2159-8290.CD-23-1073

Authors: Chunyang Bao, Richard W Tourdot, Gregory J Brunette...

The progression of precancerous lesions to malignancy is often accompanied by increasing complexity of chromosomal alterations but how these alterations arise is poorly understood. Here we perform haplotype-specific analysis of chromosomal copy-number evolution in the progression of Barrett's esophagus (BE) to esophageal adenocarcinoma (EAC) on multiregional whole-genome sequencing data of BE with dysplasia and microscopic EAC foci. We identify distinct patterns of copy-number evolution indicating multigenerational chromosomal instability that is initiated by cell division errors but propagated only after p53 loss. While abnormal mitosis, including whole-genome duplication, underlies chromosomal copy-number changes, segmental alterations display signatures of successive breakage-fusion-bridge cycles and chromothripsis of unstable dicentric chromosomes. Our analysis elucidates how multigenerational chromosomal instability generates copy-number variation in BE cells, precipitates complex alterations including DNA amplifications, and promotes their independent clonal expansion and transformation. In particular, we suggest sloping copy-number variation as a signature of ongoing chromosomal instability that precedes copy-number complexity. These findings suggest copy-number heterogeneity in advanced cancers originates from chromosomal instability in precancerous cells and such instability may be identified from the presence of sloping copy-number variation in bulk sequencing data.

Topics: Humans; Barrett Esophagus; Esophageal Neoplasms; Adenocarcinoma; Chromosomal Instability; Precancerous Conditions; Genomics; Disease Progression

PubMed: 37794034
DOI: 10.1038/s41467-023-41805-6

Authors: Devon A Lukow, Erin L Sausville, Pavit Suri...

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

Review

Authors: Zichen He, Andrew Wilson, Fenella Rich...

BACKGROUND

Cancer cell lines are invaluable model systems for biomedical research because they provide an almost unlimited supply of biological materials. However, there is considerable skepticism regarding the reproducibility of data derived from these in vitro models.

RECENT FINDINGS

Chromosomal instability (CIN) is one of the primary issues associated with cell lines, which can cause genetic heterogeneity and unstable cell properties within a cell population. Many of these problems can be avoided with some precautions. Here we review the underlying causes of CIN, including merotelic attachment, telomere dysfunction, DNA damage response defects, mitotic checkpoint defects and cell cycle disturbances.

CONCLUSION

In this review we summarize studies highlighting the consequences of CIN in various cell lines and provide suggestions on monitoring and controlling CIN during cell culture.

Topics: Humans; Mitosis; Reproducibility of Results; Chromosomal Instability; Cell Line; Neoplasms

PubMed: 37095005
DOI: 10.1002/cnr2.1822

Review

Authors: Anouk van den Brink, Maria F Suárez Peredo Rodríguez, Floris Foijer...

Chromosomal instability (CIN), an increased rate of chromosomal segregation abnormalities, drives intratumor heterogeneity and affects most human cancers. In addition to chromosome copy number alterations, CIN results in chromosome(s) (fragments) being mislocalized into the cytoplasm in the form of micronuclei. Micronuclei can be detected by cGAS, a double-strand nucleic acid sensor, which will lead to the production of the second messenger 2'3'-cGAMP, activation of an inflammatory response, and downstream immune cell activation. However, the molecular network underlying the CIN-induced inflammatory response is still poorly understood. Furthermore, there is emerging evidence that cancers that display CIN circumvent this CIN-induced inflammatory response, and thus immune surveillance. The STAT1, STAT3, and NF-κB signaling cascades appear to play an important role in the CIN-induced inflammatory response. In this review, we discuss how these pathways are involved in signaling CIN in cells and how they are intertwined. A better understanding of how CIN is being signaled in cells and how cancer cells circumvent this is of the utmost importance for better and more selective cancer treatment.

Topics: Humans; Aneuploidy; Chromosomal Instability; Neoplasms; Chromosome Aberrations; Inflammation

PubMed: 37561163
DOI: 10.1007/s10577-023-09730-y

Review

Authors: Marina V Nemtsova, Ekaterina B Kuznetsova, Irina V Bure...

According to the Cancer Genome Atlas (TCGA), gastric cancers are classified into four molecular subtypes: Epstein-Barr virus-positive (EBV+), tumors with microsatellite instability (MSI), tumors with chromosomal instability (CIN), and genomically stable (GS) tumors. However, the gastric cancer (GC) with chromosomal instability remains insufficiently described and does not have effective markers for molecular and histological verification and diagnosis. The CIN subtype of GC is characterized by chromosomal instability, which is manifested by an increased frequency of aneuploidies and/or structural chromosomal rearrangements in tumor cells. Structural rearrangements in the CIN subtype of GC are not accidental and are commonly detected in chromosomal loci, being abnormal because of specific structural organization. The causes of CIN are still being discussed; however, according to recent data, aberrations in the gene may cause CIN development or worsen its phenotype. Clinically, patients with the CIN subtype of GC demonstrate poor survival, but receive the maximum benefit from adjuvant chemotherapy. In the review, we consider the molecular mechanisms and possible causes of chromosomal instability in GC, the common rearrangements of chromosomal loci and their impact on the development and clinical course of the disease, as well as the driver genes, their functions, and perspectives on their targeting in the CIN subtype of GC.

Topics: Humans; Stomach Neoplasms; Epstein-Barr Virus Infections; Herpesvirus 4, Human; Chromosomal Instability; Microsatellite Instability

PubMed: 38069284
DOI: 10.3390/ijms242316961