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Results for “Chromosomal Instability”

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At least 19 recordsLinked to original sources
PubMed1992

No evidence for constitutional chromosome instability in testicular cancer.

Chromosome aberrations in 20 lymphocytes of 20 patients with testicular germ cell tumors (TGCT) treated with surgery alone were compared with those of 20 cells from 20 healthy controls using standard G-banding technique. No increase in structural aberrations was found in the cancer group. An unexpected finding was that of more cells with losses of chromosomes being present in the control group. These losses predominantly affected small chromosomes in the control group, whereas the pattern of chromosome loss was different in the cancer group. The literature claiming increased chromosome instability in TGCT patients is reviewed. Point estimates and 95% confidence intervals to exclude such a hypothesis based on our results were calculated.

Adult↗
PubMed2025

Surprisingly frequent chromosomal instability in cultivated peanut.

This study, the third in a three-part series, investigates whether chromosomal instability persists in cultivated peanut. The allotetraploid peanut (Arachis hypogaea; genome type AABB) originated from the hybridization and polyploidization of A. duranensis (AA) and A. ipaënsis (BB). Our first study established that this was an extremely narrow genetic origin, likely from a single hybridization event. This raised a paradox: how did such narrow genetics give rise to the phenotypic diversity seen in cultivated peanut? The second study addressed this, showing that a single neoallotetraploid spontaneously generates striking diversity, and that homoeologous exchanges-abundant in early generations following polyploidy-are a key mechanism in creating this diversity. In contrast to this early-generation instability, cultivated peanut is generally considered to be genetically stable, presumably due to selection. This third study tests whether residual instability still occurs in modern peanut. From a single plant of the highly selfed 'genome stock' of the cultivar 'Tifrunner', we advanced lineages through seven generations in a pollinator-free greenhouse. Among 233 plants, we identified three new large-scale chromosomal instability events: a large deletion on chromosome B01, associated with reduced pod width and seed weight, and two ABBB compositions involving chromosomes A02/B02 and A05/B05. With these observations in hand, we reinterpreted previously published data from two recombinant inbred populations. Together, these results indicate that at least 1% of pure pedigree A. hypogaea plants exhibit spontaneous large-scale chromosomal changes-a surprising frequency of instability that likely contributes to peanut's long-term adaptability and evolution.

Arachis↗
PubMed2025

CINner: Modeling and simulation of chromosomal instability in cancer at single-cell resolution.

Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types from the Pan-Cancer Analysis of Whole Genomes (PCAWG, [Formula: see text]). We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Analysis of inference results using CINner across cancer types in The Cancer Genome Atlas ([Formula: see text]) further reveals that the inferred selection parameters reflect the bias between tumor suppressor genes and oncogenes on specific genomic regions. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) in PCAWG uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions (chronic lymphocytic leukemia in PCAWG, [Formula: see text]). Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

Chromosomal Instability↗
PubMed2026

A system-level metastable model of cancer evolution: integrating replication stress, cell cycle deregulation and chromosomal instability.

INTRODUCTION: Cancer cell proliferation occurs within the context of persistent genomic instability. In this review, we propose the RS-CCD-CIN axis as a systems-level framework in which replication stress (RS), cell cycle deregulation (CCD) and chromosomal instability (CIN) form an interdependent triad that shapes tumour evolution. This axis represents a constrained metastable state in which genomic instability is tolerated and buffered. The objective of this review is to synthesize the current understanding of how the RS-CCD-CIN axis contributes to tumour heterogeneity, adaptability and therapy response. DISCUSSION: Evidence indicates that RS, CCD and CIN operate as a dynamic, interconnected network rather than as independent processes. Replication stress induces DNA damage and mutagenesis, while partial checkpoint disruption permits cells with unresolved lesions to proliferate. Chromosomal instability generates both structural and numerical alterations, contributing to intratumoural heterogeneity. Together, these processes facilitate adaptation to environmental and therapeutic pressures. Extrachromosomal DNA, micronuclei formation and cytosolic DNA signalling, including the cGAS-STING pathway, connect genomic instability to adaptive responses and immune modulation. Single-cell and spatial profiling reveal temporal and spatial variability in RS, CCD and CIN states, highlighting the limitations of static biomarkers. Therapeutically, targeting individual components often yields limited durability, whereas approaches that simultaneously perturb multiple aspects of the RS-CCD-CIN axis may improve clinical outcomes. CONCLUSIONS: This review highlights the RS-CCD-CIN axis as a fragile and metastable architecture that supports cancer evolution, while also being susceptible to collapse. A deeper understanding of this interconnected framework may inform the development of therapeutic strategies and enhance the management of resistance.

Humans↗
PubMed1992

Cytogenetics of primary prostatic adenocarcinoma. Clonality and chromosome instability.

We have examined 62 prostatic adenocarcinomas by conventional cytogenetic analysis. Most were primary cultures harvested in 14 days or less. The most consistent finding was a normal male diploid karyotype, found in 87% of all cells analyzed, and as the exclusive finding in 19 tumors. Nonrandom chromosomal changes included gain of chromosome 7 and loss of the Y chromosome. In addition, clonal gains of chromosomes 8, 12, and 18, and clonal losses of chromosomes 14 and 19 were noted in individual cases. Two structural clonal aberrations, a 9p+ in one case and a t(Y;22) (q11.2;p12) in another, were also seen. Ten of 62 cultures demonstrated chromosome instability, defined herein as nonclonal gain or loss of chromosomes in more than 10% of the metaphases examined from that culture. In those cases with nonclonal numerical aberrations, loss of chromosomes was more common than gain. The distribution of apparently random numeric abnormalities was similar to that of the clonal abnormalities in that the most frequent nonclonal gain was of chromosome 7 and the most frequent nonclonal loss was of the Y chromosome. Apparently random structural aberrations were observed in less than 1% of all analyzed cells. These included a 4p-,del(3)(q13), and t(1;11). The extent of apparently random aneuploidy suggests that chromosome instability characterizes cultured prostatic adenocarcinomas. An increase in the frequency of nonclonal aberrations may be an indicator of tumor origin in a predominantly diploid cell population. The coexistence of clonally aberrant, nonclonally aberrant, and normal diploid cells in culture may reflect heterogeneity of prostate tumors in vivo.

Adenocarcinoma↗
PubMed2025

Chromosomal instability by low-coverage whole-genome sequencing assay predicts prognosis in bladder cancer patients underwent radical cystectomy.

PURPOSE: To investigate chromosomal instability (CIN) in tumor tissue from radical bladder resection and to evaluate whether it can be used as a biomarker for the molecular typing of (BC). METHODS: DNA was extracted from formalin-fixed paraffin-embedded samples of 50 BC patients who were followed up to March 23 2023 using the Qiagen nucleic acid kits. We analyzed CIN in tumor of bladder by low-coverage whole genome sequencing (LC-WGS). Kaplan-Meier log-rank test was used to perform survival analysis. The association between variables and overall and progression-free survival was analyzed using the Cox proportional hazards model. RESULTS: There were 44 genome segments with statistically significant changes in copy number. CIN was significantly correlated with tumor stage, lymph node metastasis, relapse and survival status. Patients with high CIN were found to have a worse survival, with a median overall survival (OS) of 15 months. In addition, patients with high CIN were more likely to relapse, with a median progression-free survival (PFS) of 7 months. Patients with low CIN showed better OS and PFS. However, there was no significant difference in OS and PFS between T2 and T3-T4 patients. Multivariate cox regression analysis showed that high CIN was an independent predictor of OS, and high CIN and muscle invasion were independent predictors of PFS. Furthermore, patients with abnormal copy number of a single chromosome also had a poor prognosis, with a median survival of 14-30 months for OS and 5-10 months for PFS, while negative patients had a better prognosis. CONCLUSION: CIN was significantly correlated with tumor stage, lymph node metastasis, relapse and survival status of BC. Patients with high CIN or abnormal copy numbers of a single chromosome have a poor prognosis. CIN might be better than T stage in predicting the prognosis of patients with BC. Molecular typing of CIN can be used as an independent prognostic factor for BC.

Humans↗
PubMed2026

Non-coding RNAs as regulators of chromosomal instability in breast cancer.

Breast cancer is a highly heterogeneous disease characterized by extensive genomic and chromosomal instability (CIN), a hallmark that drives tumor evolution, intratumoral heterogeneity, therapeutic resistance, and poor clinical outcomes. Increasing evidence indicates that non-coding RNAs (ncRNAs) are important regulators of genome maintenance and chromosome stability. However, their specific contributions to CIN and the strength of the available evidence remain incompletely understood. This review examines the role of the major ncRNA classes, including circular RNAs, microRNAs, PIWI-interacting RNAs, small nucleolar RNAs, and long non-coding RNAs, in the regulation of CIN-related processes in breast cancer. We discuss the molecular mechanisms by which these ncRNAs regulate key pathways involved in CIN, while critically evaluating the strength of the experimental evidence supporting their functional roles. We also examine their associations with distinct breast cancer molecular subtypes and assess their potential as biomarkers and therapeutic targets, highlighting current limitations and knowledge gaps that hinder clinical translation. Collectively, the available evidence supports an emerging role for ncRNAs as regulators of CIN while underscoring the need for further mechanistic and subtype-specific studies to validate their clinical utility.

DNA repair↗
PubMedDate not supplied

DNA repair defects and chromosome instability disorders.

Xeroderma pigmentosum (XP), Fanconi anaemia (FA), ataxia telangiectasia (AT) and Bloom disease (BS) are four rare autosomal recessive disorders in which there is defective DNA repair and/or chromosome instability and proneness to malignancy. Between 80 and 90% of patients with XP have a defect, demonstrable at cell level, of excision of DNA lesions induced by ultraviolet rays, while the remainder have a cellular error of post-replication repair. XP cells are also deficient in repairing DNA damage caused by a variety of chemical mutagens. There are at least five different complementation groups of the first, or classical, type of XP (A to D, etc.) Apparently group C patients, as well as those with defective post-replication repair, do not show the progressive neurological illness found in a proportion of the other patients. AT is heterogeneous clinically and genetically. Clinically it presents with a progressive neurological illness, progressive telangiectases and a developmental disorder of the thymus. AT is characterized by sensitivity to X-rays and AT cells are unable to repair gamma-ray-induced damage to bases in the DNA. It appears that in many cases of the disorder a chromosomally marked cellular clone is found. In BS the main defect, which results in growth retardation, sun-induced lesions of the face and susceptibility to infection, appears to be a slow DNA chain maturation during DNA synthesis. An increase of sister chromatid exchanges is characteristically seen in the chromosomes of cultured BS cells. In FA, in which there is progressive pancytopenia with eventual bone marrow exhaustion and a tendency to haemorrhage and infection, the cellular defect seems to consist of faulty removal of repair of cross-links in the DNA. In this condition, as in BS and AT, various structural chromosome changes are detected in cultured cells. Patients with XP develop skin cancers in early life and often maligant melanomas. In the other three disorders, in which an immune deficiency is often present, leukaemia and related proliferative disorders are a frequent cause of death while other malignancies also occur. There is some evidence that points to an increased risk of malignancy in heterozygotes who carry the FA and AT genes.

Abnormalities, Multiple↗
PubMed1975

[Chromosomal instability in homo- and heterocygocity for microcephalia vera )author's transl)].

In a family with microcephalia vera, not only the 3 microcephalic probands, but also their healthy mother showed a significantly increased rate of spontaneous structural chromosomal aberrations in cultures of lymphocytes of the peripheral blood. Thus an increased aberration rate in the lymphocytes of asymptomatic family members could serve as a sign of heterocygocity. The qualitative analysis revealed aberrations of the chromatid and chromosomal type; exchanges that are frequently found in Fanconi's and Bloom's syndrome could not be detected. Therefore it can be assumed that the chromosomal instability of microcephalia vera is caused by a specific mechanism.

Adult↗
PubMed2025

Panorama of Chromosomal Instability in Lung Cancer.

Lung cancer is a highly heterogeneous disease primarily driven by tobacco smoking. About 20% of lung cancers occur among patients who have never smoked (LCINS) with differences in patient ancestry, sex, tumor histology, and clinical features. Our understanding of chromosomal instability in lung cancer, especially LCINS, is still limited. Here, we perform a comprehensive study of 182,429 somatic structural variations (SVs) detected in 1,209 whole-genome sequenced lung cancers, of which 864 LCINS. SVs are more abundant in tumors from patients who have smoked (LCSS); however, they are more complex and play more important roles in tumorigenesis in LCINS. EGFR mutations and KRAS mutations profoundly and independently shape the SV landscape. EGFR-mutant tumors have higher SV burden and more cancer-driving SVs. In contrast, KRAS mutations are associated with lower SV burden and less driver SVs. We decompose 16 SV signatures for both complex and simple SVs that likely represent divergent molecular mechanisms. The SV breakpoints have distinct distributions across the genome depending on the signatures due to mutagenic mechanisms and positive selection. Many established cancer-driving genes are recurrently rearranged by multiple SV signatures suggesting functional convergence of these genome instability mechanisms.

Journal Article↗
PubMed2025

Candida glabrata replicating within macrophages experiences amino acid deprivation, DNA damage, and chromosome instability.

Macrophages, the central players of innate immunity, control invading microbes by encapsulating them inside the phagosome, a nutrient-poor, reactive oxidant species-rich organelle. Nevertheless, some microbes, including the opportunistic yeast pathogen Candida glabrata, noted for its karyotype diversity, rapid evolution of antifungal drug resistance, and lack of meiosis, can survive and even replicate inside macrophages. However, it is not fully understood how C. glabrata responds to macrophage engulfment, and it is unknown how this presumably DNA-damaging environment influences the pathogen's genome stability. In this study, we used comparative transcriptomics to identify amino acid starvation and DNA damage as conditions eliciting C. glabrata responses most similar to macrophage engulfment. Consistent with this, we found that C. glabrata intra-macrophage survival and replication require master regulator of amino acid biosynthesis GCN4 and functional DNA double-strand break repair. Furthermore, comet assays provided the first direct evidence for increased DNA breaks in intra-macrophage yeast, and pulse-field gel electrophoresis showed that chromosomal alterations occur frequently in macrophage-passaged C. glabrata. Interestingly, these alterations could not be resolved by long read DNA sequencing, suggesting that they involved highly complex repetitive regions. Finally, we identified several point mutations emerging during macrophage passaging and showed that among them, a frameshift in RME1 (repressor of meiosis in Saccharomyces cerevisiae), increased C. glabrata intra-macrophage fitness. Together, these analyses point to amino acid deprivation, reveal elevated DNA breakage and chromosome instability, and raise intriguing questions about the role of meiotic gene orthologs in C. glabrata persisting and replicating within macrophages.

Journal Article↗
PubMed2026

A versatile cGAMP reporter reveals principles of cGAS activation by DNA damage and chromosome instability.

cGAS is the primary innate immune DNA sensor. On binding DNA, cGAS generates cGAMP, ultimately driving inflammation. Although normally silenced on self-DNA, genotoxic stress can activate cGAS, proposed to be mediated by micronuclei, chromosome bridges and DNA:RNA hybrids. However, mechanistically, this is poorly understood due to a lack of sensitive and selective single-cell cGAS activation assays. Here we solve this with an improved cGAMP reporter for microscopy, flow cytometry and biochemical assays. Strikingly, we find that genotoxic stress-mediated cGAS activation is a rare event that is not driven by enrichment on micronuclei and occurs by mechanisms that vary in dependence on the genotoxic stress. Following chromosome mis-segregation, cGAS activation correlates with bridge association but, notably, ionizing radiation activates cGAS independently of bridges. Whereas simple DNA:RNA hybrids are inert, more complex structures such as R-loops activate cGAS. Our work revises the cGAS signalling framework and introduces a flexible tool to examine it.

Nucleotidyltransferases↗
PubMed1975

Chromosomal instability in cell lines derived from patients with xeroderma pigmentosum.

The chromosomes of four cell lines derived from skin biopsies of four patients with xeroderma pigmentosum (XP) were studied and compared with corresponding controls. In the early passages, all XP lines had normal chromosome constitution with rates of polyploidy and chromosome aberrations within the range found in the controls. In the later passages, the XP cell lines had higher levels of chromosome abnormalities. The degree of abnormalities varied greatly among the XP lines; two lines had very high level of polyploidy (up to 50%) and cells with chromosome aberrations (up to 79%), the other two XP lines had a normal level of polyploidy and a slightly higher incidence of cells with chromosome aberrations than normal. The most common type of aberration was dicentrics.

Adolescent↗
PubMed1992

Telomere shortening associated with chromosome instability is arrested in immortal cells which express telomerase activity.

Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5. In all mortal populations, telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures. When transformed cells reached crisis, the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed. In immortal cells, telomere length and frequency of dicentric chromosomes stabilized after crisis. Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations. These results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.

Cell Transformation, Neoplastic↗