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Journal articles on the topic 'Chromosomal heterogeneity'
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Negoto, Tetsuya, Hidenobu Yoshitake, Aya Hashimoto, et al. "10049-GGE-3 CHARACTERISTICS OF CHROMOSOMAL ABERRATIONS IN GLIOMAS AND THEIR IMPACT ON RECURRENCE." Neuro-Oncology Advances 5, Supplement_5 (2023): v7. http://dx.doi.org/10.1093/noajnl/vdad141.025.
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Abstract INTRODUCTION Chromosome instability is the inability to evenly distribute sister chromatids during mitosis, which leads to chromosomal numerical/structural abnormalities and increases the genetic heterogeneity of the tumor. In this study, we investigated the association between chromosome aberration characteristics and recurrence in clinical specimens of gliomas using the Spectral Karyotyping. METHODS Chromosome karyotypes were analyzed for a total of 121 cells from 26 gliomas (Glioblastoma 14, PXA 3, Astrocytoma 5, Oligodendroglioma 3, Ependymoma 1, 18 primary cases and 8 recurrent cases) removed at our hospital. In addition, each case was quantitatively analyzed for numerical aberrations/ cell (AS: Aneuploidy score), structural abnormalities/ cell (SS: Structural abnormality score), and karyotype concordance rate between cells /case (HS: Heterogeneity Score) were quantitatively analyzed. RESULTS In the analysis of all cases, numerical aberrations in chromosomes X and 7 (21.5%/16.9%) and structural aberrations in chromosomes 1, 4, and 5 (>10.0%) were highly prevalent, with structural aberrations in large chromosomes and numerical aberrations in small chromosomes. On the other hand, quantitative analysis showed that the mean for the first occurrence (18 cases); AS: 2.22±0.94/ SS: 1.48±0.96/ HS: 22.2±7.41, and for the recurrence (8 cases); AS: 4.68±1.75/ SS: 7.50±1.44/ HS: 55.0±11.1, indicating that numerical and structural abnormalities were more common in the recurrent lesions The recurrent lesions showed more numerical and structural abnormalities and higher intra-tumor heterogeneity. In addition, in cases in which the primary/recurrent lesions were analyzed in pairs, the frequency of numerical and structural chromosomal abnormalities was higher in the recurrent lesions. DISCUSSION This study clarified the characteristics of chromosomal aberrations in each pathological classification of gliomas and suggested the involvement of chromosomal instability in the recurrence process. We look forward to further clarification of the pathogenesis of gliomas with a focus on chromosomal instability.
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Weier, Jingly F., Christy Ferlatte, Adolf Baumgartner, Ha Nam Nguyen, Beatrice A. Weier, and Heinz-Ulrich G. Weier. "Analysis of human invasive cytotrophoblasts demonstrates mosaic aneuploidy." PLOS ONE 18, no. 7 (2023): e0284317. http://dx.doi.org/10.1371/journal.pone.0284317.
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A total of 24 chromosome-specific fluorescence in situ hybridization probes for interphase nucleus analysis were developed to determine the chromosomal content of individual human invasive cytotrophoblasts derived from in vitro cultured assays. At least 75% of invasive cytotrophoblasts were hyperdiploid and the total number of chromosomes ranged from 47 to 61. The results also demonstrated that these hyperdiploid invasive cytotrophoblasts showed significant heterogeneity. The most copy number gains were observed for chromosomes 13, 14, 15, 19, 21, and 22 with average copy number greater than 2.3. A parallel study using primary invasive cytotrophoblasts also showed a similar trend of copy number changes. Conclusively, 24-chromosome analysis of human non-proliferating cytotrophoblasts (interphase nuclei) was achieved. Hyperdiploidy and chromosomal heterogeneity without endoduplication in invasive cytotrophoblasts may suggest a selective advantage for invasion and short lifespan during normal placental development.
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Iourov, Ivan Y., Svetlana G. Vorsanova, Yuri B. Yurov, and Sergei I. Kutsev. "Ontogenetic and Pathogenetic Views on Somatic Chromosomal Mosaicism." Genes 10, no. 5 (2019): 379. http://dx.doi.org/10.3390/genes10050379.
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Intercellular karyotypic variability has been a focus of genetic research for more than 50 years. It has been repeatedly shown that chromosome heterogeneity manifesting as chromosomal mosaicism is associated with a variety of human diseases. Due to the ability of changing dynamically throughout the ontogeny, chromosomal mosaicism may mediate genome/chromosome instability and intercellular diversity in health and disease in a bottleneck fashion. However, the ubiquity of negligibly small populations of cells with abnormal karyotypes results in difficulties of the interpretation and detection, which may be nonetheless solved by post-genomic cytogenomic technologies. In the post-genomic era, it has become possible to uncover molecular and cellular pathways to genome/chromosome instability (chromosomal mosaicism or heterogeneity) using advanced whole-genome scanning technologies and bioinformatic tools. Furthermore, the opportunities to determine the effect of chromosomal abnormalities on the cellular phenotype seem to be useful for uncovering the intrinsic consequences of chromosomal mosaicism. Accordingly, a post-genomic review of chromosomal mosaicism in the ontogenetic and pathogenetic contexts appears to be required. Here, we review chromosomal mosaicism in its widest sense and discuss further directions of cyto(post)genomic research dedicated to chromosomal heterogeneity.
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Woodward, Eleanor L., Minjun Yang, Larissa H. Moura-Castro, et al. "Genomic Heterogeneity and Clonal Evolution in High Hyperdiploid Childhood Acute Lymphoblastic Leukemia." Blood 138, Supplement 1 (2021): 3489. http://dx.doi.org/10.1182/blood-2021-145521.
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Abstract High hyperdiploid (HeH) B-cell precursor acute lymphoblastic leukemia (BCP ALL) is characterized by a very specific nonrandom gain of chromosomes; a feature distinct from other types of aneuploid tumor types that usually display very heterogeneous gains and losses of chromosomes. Gains of chromosomes X, 4, 6, 10, 14, 17, and 18 are seen in more than 75% of cases of HeH childhood ALL, and of chromosome 21 in 100% of cases. In contrast to many aneuploid malignancies, there has been little evidence of chromosomal instability (CIN) in HeH ALL and the mechanisms leading to these chromosomal gains remain unknown. The aim of this project was to determine the level of genomic heterogeneity in HeH ALL. In order to do this, we performed low-pass whole genome sequencing (WGS) of single cells isolated from diagnostic bone marrow samples from HeH ALL patients to investigate cell-to-cell heterogeneity. Single nuclei in G 1 phase from nine diagnostic childhood HeH ALL samples were isolated using fluorescence-activated cell sorting and DNA libraries were constructed for low-pass WGS. Copy number analysis for each individual cell was performed in-house using the software programs AneuFinder and Ginkgo. Homolog inheritance of chromosomes gained or lost was determined by screening for heterozygous variants and calculation of the variant allele frequencies (VAF). Sequencing 2,572 single cells showed that the nine HeH ALL patients were all relatively homogenous at the trunk of their evolution tree and that the bulk of chromosomal gains were stable and unchanging. Structural aberrations, visible as partial chromosome copy number changes, were detected at diagnosis in most cases, with a greater number of structural aberrations detected in patients with greater numbers of sub-clones (defined as three or more cells presenting with the same numerical and structural aberrations). Unique numerical chromosomal aberrations detected in two or fewer cells were relatively random and therefore indicative of nondisjunction events in recent cell divisions rather than being part of the clonal evolution of the leukemia. These results indicate very low heterogeneity in HeH ALL and suggests that the genome of these leukemias is relatively stable. Disclosures No relevant conflicts of interest to declare.
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Cruz, Vanessa Paes da, Cristiane Kioko Shimabukuro-Dias, Claudio Oliveira, and Fausto Foresti. "Karyotype description and evidence of multiple sex chromosome system X1X1X2X2/X1X2Y in Potamotrygon aff. motoro and P. falkneri (Chondrichthyes: Potamotrygonidae) in the upper Paraná River basin, Brazil." Neotropical Ichthyology 9, no. 1 (2011): 201–8. http://dx.doi.org/10.1590/s1679-62252011000100020.
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Cytogenetic analysis of Potamotrygon aff. motoro and P. falkneri indicated the occurrence of an X1X1X2X2/X1X2 Y multiple sex chromosome system in both species, with 2n = 66 chromosomes for females and 2n = 65 chromosomes for males. The nucleolus organizer regions (NORs) identified using Ag-NOR technique showed that both species have multiple Ag-NORs (5 to 7 chromosomes stained). C-banding technique indicated the presence of heterochromatic blocks in the centromeric regions of almost all chromosomes in both species. Through this study there was evidence of heterogeneity in the karyotypes, which suggests that chromosomal rearrangements such as inversions and/or translocations occurred during the chromosomal evolution in two species of this genus.
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Roschke, Anna. "Abstract B032: Comprehensive analysis of clonality, segregation errors, chromosomal instability and heterogeneity in cancer cell lines and cancer samples reveals that cancer evolution is often promoted by highly aberrant cellular divisions." Cancer Research 84, no. 3_Supplement_2 (2024): B032. http://dx.doi.org/10.1158/1538-7445.canevol23-b032.
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Abstract Chromosomal instability (CIN) is the most common form of genomic instability in cancer. CIN leads to structural and numerical chromosomal aberrations and to heterogeneity of such aberrations inside the same tumor. Together with other forms of genomic and epigenomic instability, CIN underlies the most dangerous feature of cancer cells, namely, ability to evolve, allowing cancer cells to evade immunologic surveillance, to metastasize, to become resistant to drug treatments. Studies of chromosomal instability are significantly impeded by the lack of comprehensive approaches for simultaneous detection of different forms of ongoing chromosomal instability and their outcomes. We developed an approach that allows to analyze the clonal composition and chromosomal heterogeneity in cell lines and cancer samples, as well as rates of different forms of ongoing chromosomal instability in cancer cell lines. At the heart our analysis is a multiplex interphase FISH (miFISH) with seven sequential hybridizations of color probe panels resulting in the assessment of a total of 35 probes per single cell. Each probe panel is designed to include the centromeric probe and probes on the p- and q-arm for a given chromosome that allows for the simultaneous assessment of centromeric probes and gene-specific arm probes. This approach was applied to interphase nuclei, metaphase spreads and bi-nucleated/dividing cancer cells in colorectal and cervical cell lines and cancer samples. miFISH allows for automated acquisition of nuclei and metaphase spreads on a BioView spotcounting system. A gallery provides detailed views for semi-automatic as well as manual analysis of the obtained images. A total of 10000-25000 cell images were collected from each slide. The simultaneous evaluation of our strategically chosen centromeric and gene-specific probes within the same cells allows unprecedented insights in the patterns of distribution of genetic material among cancer cells in cancer cell population, and, especially, in dividing cells. We evaluated clonality, clonal and non-clonal chromosomal heterogeneity, ploidy distributions, and occurrence of endoreplication. Assessment of dividing cells based on equal or unequal distribution of miFISH centromeric and gene-specific signals allowed to estimate and compare the rates and outcomes of different forms of ongoing chromosomal instability such as structural rearrangements and amplifications, loss of chromosomes or chromosomal fragments in micronuclei, non-disjunctions, grossly asymmetrical cell divisions (including multipolar mitoses). Conclusions: Gradual changes in chromosomal/genomic content of cancer cells occur due to structural rearrangements, losses of chromosomes and chromosomal fragments in micronuclei, and by relatively rare single chromosome non-disjunctions. Grossly abnormal cell divisions (massive non-disjunctions and structural rearrangements) is the main source for the high level of chromosomal abnormalities and aneuploidy in evolved cancer cell populations. Citation Format: Anna Roschke. Comprehensive analysis of clonality, segregation errors, chromosomal instability and heterogeneity in cancer cell lines and cancer samples reveals that cancer evolution is often promoted by highly aberrant cellular divisions [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr B032.
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Ognibene, Marzia, Patrizia De Marco, Loredana Amoroso, et al. "Neuroblastoma Patients’ Outcome and Chromosomal Instability." International Journal of Molecular Sciences 24, no. 21 (2023): 15514. http://dx.doi.org/10.3390/ijms242115514.
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Chromosomal instability (CIN) induces a high rate of losses or gains of whole chromosomes or parts of chromosomes. It is a hallmark of most human cancers and one of the causes of aneuploidy and intra-tumor heterogeneity. The present study aimed to evaluate the potential prognostic role of CIN in NB patients at diagnosis. We performed array comparative genomic hybridization analyses on 451 primary NB patients at the onset of the disease. To assess global chromosomal instability with high precision, we focused on the total number of DNA breakpoints of gains or losses of chromosome arms. For each tumor, an array-CGH-based breakpoint instability index (BPI) was assigned which defined the total number of chromosomal breakpoints per genome. This approach allowed us to quantify CIN related to whole genome disruption in all NB cases analyzed. We found differences in chromosomal breakages among the NB clinical risk groups. High BPI values are negatively associated with survival of NB patients. This association remains significant when correcting for stage, age, and MYCN status in the Cox model. Stratified analysis confirms the prognostic effect of BPI index in low-risk NB patients with non-amplified MYCN and with segmental chromosome aberrations.
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Al-Ardi, Musafer. "Illumination on the structure and characteristics of Entamoeba histolytica genome." Al-Qadisiyah Journal Of Pure Science 26, no. 4 (2021): 19–26. http://dx.doi.org/10.29350/qjps.2021.26.4.1311.
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Entamoeba histolytica, likes other Organismes, is characterized by diversity and heterogeneity in its genetic content, which is one of the most paramount reasons for survival, and the increase in susceptibility to infection. Non-condensation of chromosomes during the process of cell division and the ambiguity of the chromosomal ploidy makes predicting the exact chromosomal numeral difficult. Genes distributed across 14 chromosomes as well as many extra-chromosome elements. Most Genes compose of one axon only, with Introns in 25% of Genes. This genome is characterized by the presence of Polymorphic internal repeat regions, and several gene families, one of these large families encoding Transmembrane kinas, Cysteine protease (CP), SREHP protein, and others.
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Gijtenbeek, Johanna M. M., Bram Jacobs, Sandra H. E. Sprenger, et al. "Analysis of von Hippel—Lindau mutations with comparative genomic hybridization in sporadic and hereditary hemangioblastomas: possible genetic heterogeneity." Journal of Neurosurgery 97, no. 4 (2002): 977–82. http://dx.doi.org/10.3171/jns.2002.97.4.0977.
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Object. Hemangioblastomas (HBs) occur sporadically or as a manifestation of von Hippel—Lindau (VHL) disease. In the majority of VHL-related HBs, inactivation of the VHL tumor suppressor gene (TSG), which is located on chromosome 3p25–26, is found. The VHL gene is assumed to be involved also in the development of sporadic HBs. In a previous study of chromosomal aberrations of sporadic HBs, multiple chromosomal imbalances were found in the majority of tumors. The aim of this study was to analyze further both sporadic HBs and VHL-related HBs to determine if these histopathologically identical tumors have a different genetic background. Methods. Sixteen sporadic HBs and seven VHL-related HBs were identified by clinical criteria and analyzed. Comparative genomic hybridization was used to screen for chromosomal imbalances throughout the entire HB genome. Additionally, mutation analysis of the VHL gene was performed using direct sequencing. Loss of chromosome 3 and multiple other chromosomal imbalances were found in the sporadic HBs, although only one imbalance, a loss of chromosome 3, was detected in the seven VHL-related HBs. Somatic VHL gene mutations were found in one third of sporadic HBs, whereas a mutation of the VHL gene was detected in all VHL-related HBs. Conclusions. These results indicate that the molecular mechanisms underlying sporadic HBs and VHL-related HBs are different. Inactivation of the VHL gene is probably not the most important event in the tumorigenesis of sporadic HBs. Other mechanisms of inhibition of VHL protein function, or inactivation of other TSGs, on chromosome 3p or on other chromosomes, might be important in the development of sporadic HBs.
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Eidelman, Yuri, Ilya Salnikov, Svetlana Slanina, and Sergey Andreev. "Chromosome Folding Promotes Intrachromosomal Aberrations under Radiation- and Nuclease-Induced DNA Breakage." International Journal of Molecular Sciences 22, no. 22 (2021): 12186. http://dx.doi.org/10.3390/ijms222212186.
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The long-standing question in radiation and cancer biology is how principles of chromosome organization impact the formation of chromosomal aberrations (CAs). To address this issue, we developed a physical modeling approach and analyzed high-throughput genomic data from chromosome conformation capture (Hi-C) and translocation sequencing (HTGTS) methods. Combining modeling of chromosome structure and of chromosomal aberrations induced by ionizing radiation (IR) and nuclease we made predictions which quantitatively correlated with key experimental findings in mouse chromosomes: chromosome contact maps, high frequency of cis-translocation breakpoints far outside of the site of nuclease-induced DNA double-strand breaks (DSBs), the distinct shape of breakpoint distribution in chromosomes with different 3D organizations. These correlations support the heteropolymer globule principle of chromosome organization in G1-arrested pro-B mouse cells. The joint analysis of Hi-C, HTGTS and physical modeling data offers mechanistic insight into how chromosome structure heterogeneity, globular folding and lesion dynamics drive IR-recurrent CAs. The results provide the biophysical and computational basis for the analysis of chromosome aberration landscape under IR and nuclease-induced DSBs.
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Schoen, Daniel J. "Comparative Genomics, Marker Density and Statistical Analysis of Chromosome Rearrangements." Genetics 154, no. 2 (2000): 943–52. http://dx.doi.org/10.1093/genetics/154.2.943.
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Abstract Estimates of the number of chromosomal breakpoints that have arisen (e.g., by translocation and inversion) in the evolutionary past between two species and their common ancestor can be made by comparing map positions of marker loci. Statistical methods for doing so are based on a random-breakage model of chromosomal rearrangement. The model treats all modes of chromosome rearrangement alike, and it assumes that chromosome boundaries and breakpoints are distributed randomly along a single genomic interval. Here we use simulation and numerical analysis to test the validity of these model assumptions. Mean estimates of numbers of breakpoints are close to those expected under the random-breakage model when marker density is high relative to the amount of chromosomal rearrangement and when rearrangements occur by translocation alone. But when marker density is low relative to the number of chromosomes, and when rearrangements occur by both translocation and inversion, the number of breakpoints is underestimated. The underestimate arises because rearranged segments may contain markers, yet the rearranged segments may, nevertheless, be undetected. Variances of the estimate of numbers of breakpoints decrease rapidly as markers are added to the comparative maps, but are less influenced by the number or type of chromosomal rearrangement separating the species. Variances obtained with simulated genomes comprised of chromosomes of equal length are substantially lower than those obtained when chromosome size is unconstrained. Statistical power for detecting heterogeneity in the rate of chromosomal rearrangement is also investigated. Results are interpreted with respect to the amount of marker information required to make accurate inferences about chromosomal evolution.
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Roschke, Anna, Darawalee Wangsa, Nina Gutzeit, et al. "Abstract 3890: Novel miFISH single-cell approach gives new insights into chromosomal instability and evolution of colorectal cancers." Cancer Research 85, no. 8_Supplement_1 (2025): 3890. https://doi.org/10.1158/1538-7445.am2025-3890.
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Abstract Introduction: Chromosomal instability (CIN) is the predominant form of genomic instability in cancers, characterized by both numerical and structural alterations of chromosomes. CIN is crucial for the most threatening aspect of cancers: their ability to evolve, allowing them to circumvent immune detection, metastasize, develop resistance to therapies, and lead to treatment failure. At the same time, the CIN phenotype could provide valuable targets for cancer therapy. We developed a multiplex FISH (miFISH) method to study heterogeneity and ongoing CIN in cancer cells. The objective of our research was to determine whether high-grade aneuploidy develops through sequential or abrupt changes in chromosomal content, a question previously unexplored due to the absence of comprehensive methods for simultaneously detecting different forms of ongoing CIN on a single-cell level. Experimental Procedure: Sequential hybridizations of miFISH panels allow the assessment of up to 35 probes per single cell. Each panel was designed to include the centromeric probe and gene-specific probes on the p- and q-arm for a given chromosome. This approach was applied to colorectal cancer cell lines (with and without microsatellite instability) and colorectal cancer samples. A total of 10000-25000 targets were collected from each slide. Analysis was done by counting of signals in mononucleated cells, binucleated/dividing cells and metaphase spreads. Results: The simultaneous evaluation of centromeric and gene-specific sets of miFISH probes led to unprecedented insights into the patterns of distribution of chromosomal content among individual cells, and, especially, in dividing cells. We compared different forms of ongoing CIN: structural rearrangements, formation of micronuclei with whole chromosomes or chromosomal fragments, non-disjunctions of chromosomes, grossly asymmetrical cell divisions, including divisions with ploidy changes and multipolar mitoses. We observed that gradual changes in chromosomal/genomic content occur primarily due to frequent structural rearrangements, less frequent chromosome or fragment losses in micronuclei, and very rare single chromosome non-disjunctions. Of note, grossly abnormal cell divisions, characterized by massive non-disjunctions and structural rearrangements, occur with relatively high frequency. The same patterns of chromosomal heterogeneity and instability have been observed in cancer cell lines and in tumor samples. Conclusions: The novel miFISH approach applied to studies of chromosomal instability in colorectal cancers and cell lines revealed multiple paths leading to chromosomal diversification of cancer cell populations. Grossly abnormal cell divisions are likely to contribute to high-level aneuploidies and ploidy changes, and could underlie the rapid evolution of cancer under selective pressure. Citation Format: Anna Roschke, Darawalee Wangsa, Nina Gutzeit, Richard Korshkov, Tim Thoerner, Kerstin Heselmeyer-Haddad, Paul Meltzer. Novel miFISH single-cell approach gives new insights into chromosomal instability and evolution of colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3890.
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Lo, Anthony W. I., Carl N. Sprung, Bijan Fouladi, et al. "Chromosome Instability as a Result of Double-Strand Breaks near Telomeres in Mouse Embryonic Stem Cells." Molecular and Cellular Biology 22, no. 13 (2002): 4836–50. http://dx.doi.org/10.1128/mcb.22.13.4836-4850.2002.
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ABSTRACT Telomeres are essential for protecting the ends of chromosomes and preventing chromosome fusion. Telomere loss has been proposed to play an important role in the chromosomal rearrangements associated with tumorigenesis. To determine the relationship between telomere loss and chromosome instability in mammalian cells, we investigated the events resulting from the introduction of a double-strand break near a telomere with I-SceI endonuclease in mouse embryonic stem cells. The inactivation of a selectable marker gene adjacent to a telomere as a result of the I-SceI-induced double-strand break involved either the addition of a telomere at the site of the break or the formation of inverted repeats and large tandem duplications on the end of the chromosome. Nucleotide sequence analysis demonstrated large deletions and little or no complementarity at the recombination sites involved in the formation of the inverted repeats. The formation of inverted repeats was followed by a period of chromosome instability, characterized by amplification of the subtelomeric region, translocation of chromosomal fragments onto the end of the chromosome, and the formation of dicentric chromosomes. Despite this heterogeneity, the rearranged chromosomes eventually acquired telomeres and were stable in most of the cells in the population at the time of analysis. Our observations are consistent with a model in which broken chromosomes that do not regain a telomere undergo sister chromatid fusion involving nonhomologous end joining. Sister chromatid fusion is followed by chromosome instability resulting from breakage-fusion-bridge cycles involving the sister chromatids and rearrangements with other chromosomes. This process results in highly rearranged chromosomes that eventually become stable through the addition of a telomere onto the broken end. We have observed similar events after spontaneous telomere loss in a human tumor cell line, suggesting that chromosome instability resulting from telomere loss plays a role in chromosomal rearrangements associated with tumor cell progression.
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Mason, Frank M., Anteneh T. Tebeje, Emily S. Kounlavong, et al. "Abstract PR012: SETD2 safeguards the genome against isochromosome formation." Cancer Research 83, no. 16_Supplement (2023): PR012. http://dx.doi.org/10.1158/1538-7445.kidney23-pr012.
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Abstract Chromosome mis-segregation during cell division occurs in diverse tumor types, promoting aneuploidy and intratumoral genetic heterogeneity. While the mechanisms that govern chromosome segregation are well-established, how changes in the activities of tumor suppressors or oncogenes drive mitotic errors remain poorly understood. Loss of the tumor suppressor SETD2, the methyltransferase responsible for tri-methylation of histone 3 lysine 36 (H3K36me3), correlates with clear cell renal cell carcinoma (ccRCC) tumors exhibiting extensive intratumoral heterogeneity. Yet, how loss of H3K36me3 or SETD2 promotes heterogeneity is unknown. Here, we show that loss of SETD2 promotes chromosome mis-segregation during mitosis and interphase DNA bridges driven by the formation of dicentric chromosomes. Cytogenetic analyses revealed that these dicentrics loss were largely comprised of mirror-imaged isodicentric chromosomes that contain two active centromeres. In addition to isodicentrics, cells lacking SETD2 or H36K36me3 generated iso- and acentric chromosomes, however loss of SETD2 protein additionally caused chromosome instability. These data directly link loss of a tumor suppressor to these mutable chromatin structures that initiate intratumor heterogeneity by promoting gross chromosomal rearrangements. Citation Format: Frank M. Mason, Anteneh T. Tebeje, Emily S. Kounlavong, Rashmi Dahiya, Logan Vlach, Tiffany Guess, Ruhee Dere, Ryoma Ohi, Peter Ly, Cheryl L. Walker, W. Kimryn Rathmell. SETD2 safeguards the genome against isochromosome formation [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR012.
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Aldana-Salazar, Fernando, Nelson Rangel, María José Rodríguez, César Baracaldo, María Martínez-Agüero, and Milena Rondón-Lagos. "Chromosomal Damage, Chromosome Instability, and Polymorphisms in GSTP1 and XRCC1 as Biomarkers of Effect and Susceptibility in Farmers Exposed to Pesticides." International Journal of Molecular Sciences 25, no. 8 (2024): 4167. http://dx.doi.org/10.3390/ijms25084167.
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In the department of Boyacá, Colombia, agriculture stands as one of the primary economic activities. However, the escalating utilization of pesticides within this sector has sparked concern regarding its potential correlation with elevated risks of genotoxicity, chromosomal alterations, and carcinogenesis. Furthermore, pesticides have been associated with a broad spectrum of genetic polymorphisms that impact pivotal genes involved in pesticide metabolism and DNA repair, among other processes. Nonetheless, our understanding of the genotoxic effects of pesticides on the chromosomes (as biomarkers of effect) in exposed farmers and the impact of genetic polymorphisms (as susceptibility biomarkers) on the increased risk of chromosomal damage is still limited. The aim of our study was to evaluate chromosomal alterations, chromosomal instability, and clonal heterogeneity, as well as the presence of polymorphic variants in the GSTP1 and XRCC1 genes, in peripheral blood samples of farmers occupationally exposed to pesticides in Aquitania, Colombia, and in an unexposed control group. Our results showed statistically significant differences in the frequency of numerical chromosomal alterations, chromosomal instability, and clonal heterogeneity levels between the exposed and unexposed groups. In addition, we also found a higher frequency of chromosomal instability and clonal heterogeneity in exposed individuals carrying the heterozygous GSTP1 AG and XRCC1 (exon 10) GA genotypes. The evaluation of chromosomal alterations and chromosomal instability resulting from pesticide exposure, combined with the identification of polymorphic variants in the GSTP1 and XRCC1 genes, and further research involving a larger group of individuals exposed to pesticides could enable the identification of effect and susceptibility biomarkers. Such markers could prove valuable for monitoring individuals occupationally exposed to pesticides.
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Woodruff, Gavin C., and Anastasia A. Teterina. "Degradation of the Repetitive Genomic Landscape in a Close Relative of Caenorhabditis elegans." Molecular Biology and Evolution 37, no. 9 (2020): 2549–67. http://dx.doi.org/10.1093/molbev/msaa107.
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Abstract The abundance, diversity, and genomic distribution of repetitive elements is highly variable among species. These patterns are thought to be driven in part by reproductive mode and the interaction of selection and recombination, and recombination rates typically vary by chromosomal position. In the nematode Caenorhabditis elegans, repetitive elements are enriched at chromosome arms and depleted on centers, and this mirrors the chromosomal distributions of other genomic features such as recombination rate. How conserved is this genomic landscape of repeats, and what evolutionary forces maintain it? To address this, we compared the genomic organization of repetitive elements across five Caenorhabditis species with chromosome-level assemblies. As previously reported, repeat content is enriched on chromosome arms in most Caenorhabditis species, and no obvious patterns of repeat content associated with reproductive mode were observed. However, the fig-associated C. inopinata has experienced repetitive element expansion and reveals no association of global repeat density with chromosome position. Patterns of repeat superfamily specific distributions reveal this global pattern is driven largely by a few repeat superfamilies that in C. inopinata have expanded in number and have weak associations with chromosome position. Additionally, 15% of predicted protein-coding genes in C. inopinata align to transposon-related proteins. When these are excluded, C. inopinata has no enrichment of genes in chromosome centers, in contrast to its close relatives who all have such clusters. Forward evolutionary simulations reveal that chromosomal heterogeneity in recombination rate alone can generate structured repetitive genomic landscapes when insertions are weakly deleterious, whereas chromosomal heterogeneity in the fitness effects of transposon insertion can promote such landscapes across a variety of evolutionary scenarios. Thus, patterns of gene density along chromosomes likely contribute to global repetitive landscapes in this group, although other historical or genomic factors are needed to explain the idiosyncrasy of genomic organization of various transposable element taxa within C. inopinata. Taken together, these results highlight the power of comparative genomics and evolutionary simulations in testing hypotheses regarding the causes of genome organization.
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Hervé, Avet-Loiseau, Magrangeas Florence, Moreau Philippe, et al. "Molecular Heterogeneity of Multiple Myeloma: Pathogenesis, Prognosis, and Therapeutic Implications." Journal of Clinical Oncology 29, no. 14 (2011): 1893–97. http://dx.doi.org/10.1200/jco.2010.32.8435.
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Multiple myeloma (MM) is characterized by a significant heterogeneity at the molecular level. The first level is the chromosomal one. Although cytogenetics is difficult to assess in MM, patients can be divided into two categories: hyperdiploidy and non-hyperdiploidy (about half in each group). Using molecular cytogenetic techniques, several subgroups of patients are identified, particularly on the basis of 14q32 translocations. This chromosomal heterogeneity is confirmed by genomic techniques (gene expression profiling or single nucleotide polymorphism/comparative genomic hybridization arrays). Unsupervised analyses of gene expression profiles identified several subgroups of patients, essentially on the basis of chromosomal abnormalities such as hyperdiploidy or 14q32 translocations. However, these analyses failed to separate MM into subentities, which could lead to specific therapeutic approaches, as is the case for non-Hodgkin's lymphomas. Nevertheless, these chromosomal/genomic data can be used for prognostication of patients. Specific chromosomal changes, such as loss of the short arm of chromosome 17, or specific gene expression profiles clearly identify patients with short survival. No molecular change so far has been associated with long survival or even cure, probably because of the short follow-up observed in all studies. So far, it is unclear how to use this massive amount of data to treat patients. Because of the complex and heterogeneous picture of the molecular profiles, it is unexpected that targeted therapies might play a role in MM. The only recognized indication is to propose bortezomib-based approaches for the treatment of patients displaying the translocation t(4;14).
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Babu, Arvind, and Ram S. Verma. "Characterization of human chromosomal constitutive heterochromatin." Canadian Journal of Genetics and Cytology 28, no. 5 (1986): 631–44. http://dx.doi.org/10.1139/g86-093.
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The constitutive heterochromatin of human chromosomes is evaluated by various selective staining techniques, i.e., CBG, G-11, distamycin A plus 4,6-diamidino-2-phenylindole-2-HCl (DA/DAPI), the fluorochrome D287/170, and Giemsa staining following the treatments with restriction endonucleases AluI and HaeIII. It is suggested that the constitutive heterochromatin could be arbitrarily divided into at least seven types depending on the staining profiles expressed by different regions of C-bands. The pericentromeric C-bands of chromosomes 1, 5, 7, 9, 13–18, and 20–22 consist of more than one type of chromatin, of which chromosome 1 presents the highest degree of heterogeneity. Chromosomes 3 and 4 show relatively less consistent heterogeneous fractions in their C-bands. The C-bands of chromosomes 10, 19, and the Y do not have much heterogeneity but have characteristic patterns with other methods using restriction endonucleases. Chromosomes 2, 6, 8, 11, 12, and X have homogeneous bands stained by the CBG technique only. Among the chromosomes with smaller pericentric C-bands, chromosome 18 shows frequent heteromorphic variants for the size and position (inversions) of the AluI resistant fraction of C-band. The analysis of various types of heterochromatin with respect to specific satellite and nonsatellite DNA sequences suggest that the staining profiles are probably related to sequence diversity.Key words: polymorphism, heteromorphism, heterogeneity, banding, restriction endonucleases.
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Loiseau, Herve Avet, Nikhil C. Munshi, Cheng Li, et al. "High-Resolution Genomic Profiles Identify Novel Genes and/or Chromosomal Regions with Prognostic and Oncogenic Significance in Myeloma Patients." Blood 110, no. 11 (2007): 657. http://dx.doi.org/10.1182/blood.v110.11.657.657.
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Abstract Despite major improvements in the treatment of myeloma over the last decade, disease course is variable due to genetic heterogeneity. Even though cytogenetics is a difficult art in myeloma, chromosomal abnormalities are present in 100% of the patients. In order to define the spectrum of unbalanced chromosomal abnormalities in myeloma, we studied a cohort of 200 patients ≤ 65 years of age, homogeneously treated with high dose chemotherapy in the IFM 99 trials, using the Affymetrix 500K SNP arrays. Bone marrow was obtained at diagnosis, and plasma cells were sorted using anti-CD138-coated magnetic beads. In all cases, a plasma cell suspension with a purity > 90% was obtained, and DNA was extracted using standard methods. After labeling, DNA was hybridized on the two Nsp and Sty chips, containing 260,000 SNP each. As expected, copy number variations were observed in all the cases. The most frequently involved chromosomes were chromosomes 13, 16, 1, 8 and 6. We then performed a prognostic analysis to correlate survival and chromosomal abnormalities. Many previously unreported chromosomal regions were identified; for example, 89 deleted chromosomal regions as well as 53 regions present in > 2.5 copies were associated with a survival < 3 years. Among the deleted regions with prognostic impact, the most frequent were 1p, 12p, and 4q. The most frequently gained regions associated with overall survival were 1q, 8q, and chromosomes 7 and 21. A similar analysis was performed for association with event free survival (EFS). Losses at 11q, 4q, and 12p were highly predictive of a short EFS, whereas gains of chromosome 15 predicted a longer EFS. Global analysis revealed a marked heterogeneity in the gains observed in hyperdiploid karyotypes, explaining the inconsistency in the literature regarding the prognostic value of hyperdiploidy. A more detailed analysis identified more than 80 genes presenting a double deletion, suggesting their role as putative tumor suppressor genes. This study represents the largest cohort of patients analyzed with such high-density arrays, enabling the description of a highly confident landscape of chromosomal abnormalities in myeloma. Moreover, since all the 200 patients were treated with a similar high-dose regimen, it allows powerful statistical analysis of the impact of chromosomal gains and losses on response to therapy, event free survival and overall survival. Finally, since all the patients were also annotated for other prognostic parameters such as t(4;14) or beta2-microglobulin, a multivariate prognostic model will be presented.
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Heng, H. H. Q., G. Liu, J. B. Stevens, et al. "Karyotype Heterogeneity and Unclassified Chromosomal Abnormalities." Cytogenetic and Genome Research 139, no. 3 (2013): 144–57. http://dx.doi.org/10.1159/000348682.
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Nordenson, Ingrid, Börje Ljungberg, and Göran Roos. "29 Chromosomal heterogeneity in renal cancer." Cancer Genetics and Cytogenetics 28, no. 1 (1987): 36. http://dx.doi.org/10.1016/0165-4608(87)90308-6.
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Negoto, Tetsuya, Satoru Komaki, Aya Hashimoto, et al. "CBMS-4 CHROMOSOMAL INSTABILITY IN GLIOMA USING SPECTRAL KARYOTYPING METHOD." Neuro-Oncology Advances 4, Supplement_3 (2022): iii1—iii2. http://dx.doi.org/10.1093/noajnl/vdac167.003.
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Abstract Introduction Chromosomal instability, the cell condition in which chromosome mis-segregation occur at a high frequency during cell division, has been considered to be involved in the molecular mechanisms that give rise to the complex genetic background of glioma. However, most of this phenomenon has been based on researches using cell line, and there have been few studies of chromosomal instability in clinical specimens of gliomas. Methods Primary cell culture was obtained from 11 glioma specimens (eight Glioblastoma (GBM), one Anaplastic PXA (aPXA), one Astrocytoma, and one Ependymoma), which was removed at our hospital, and chromosomes of up to five cells per case were analyzed by the SKY method. Chromosome instability was quantified by two parameters, one was AS (Aneuploidy score), which means the number of gain or loss of whole of the chromosome, and the other was SS: Structural abnormality score, which means the number of chromosome structural abnormality per cell. In addition, the phenotypes, which were characteristic of chromosomal instability were observed individually. Results Each quantitative value was as follows: GBM; AS:2.30±0.51 /SS:1.64±0.38, aPXA; AS :1.40±1.33 / SS:8.20±0.99, Astrocytoma and Ependymoma; AS:0.00 /SS:0.00, suggesting that chromosomal instability was associated with GBM and aPXA. Chromosome 7 amplification was most frequent in GBM (57%), and Mosaic loss of chromosome Y was also observed in 60% of males. Some characteristic karyotypes which suggest the phenomenon of Chromothripsis or Double minute were also observed. The karyotype concordance rate in the cases with p53 mutation was 60%, and that with p53 wild type was 100%, indicating that the p53 mutation increased the genotype heterogeneity in the same specimen. Discussion In clinical specimens of gliomas, aneuploidy and structural abnormalities were identified in GBM and aPXA, suggesting that chromosomal instability contributes to their cellular phenotype and malignancy.
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Del Rey, Javier, Mónica Santos, Antonio González-Meneses, Montserrat Milà, and Carme Fuster. "Heterogeneity of a Constitutional Complex Chromosomal Rearrangement in 2q." Cytogenetic and Genome Research 148, no. 2-3 (2016): 156–64. http://dx.doi.org/10.1159/000445859.
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Complex chromosome rearrangements (CCRs) are unusual structural chromosome alterations found in humans, and to date only a few have been characterized molecularly. New mechanisms, such as chromothripsis, have been proposed to explain the presence of the CCRs in cancer cells and in patients with congenital disorders and/or mental retardation. The aim of the present study was the molecular characterization of a constitutional CCR in a girl with multiple congenital disorders and intellectual disability in order to determine the genotype-phenotype relation and to clarify whether the CCR could have been caused by chromosomal catastrophic events. The present CCR was characterized by G-banding, high-resolution CGH, multiplex ligation-dependent probe amplification and subtelomeric 2q-FISH analyses. Preliminary results indicate that the de novo CCR is unbalanced showing a 2q37.3 deletion and 2q34q37.2 partial trisomy. Our patient shows some of the typical traits and intellectual disability described in patients with 2q37 deletion and also in carriers of 2q34q37.2 partial trisomy; thus, the clinical disorders could be explained by additional effects of both chromosome alterations (deletions and duplications). A posterior, sequential FISH study using BAC probes revealed the unexpected presence of at least 17 different reorganizations affecting 2q34q37.2, suggesting the existence of chromosome instability in this region. The present CCR is the first case described in the literature of heterogeneity of unbalanced CCRs affecting a small region of 2q, indicating that the mechanisms involved in constitutional chromosome rearrangement may be more complex than previously thought.
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Duesberg, Peter, Ruhong Li, Alice Fabarius, and Ruediger Hehlmann. "The Chromosomal Basis of Cancer." Analytical Cellular Pathology 27, no. 5-6 (2005): 293–318. http://dx.doi.org/10.1155/2005/951598.
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Conventional genetic theories have failed to explain why cancer (1) is not heritable and thus extremely rare in newborns, (2) is caused by non-mutagenic carcinogens, (3) develops only years to decades after initiation by carcinogens, (4) follows pre-neoplastic aneuploidy, (5) is aneuploid, (6) is chromosomally and phenotypically “unstable”, (7) carries specific aneusomies, (8) generates much more complex phenotypes than conventional mutation such as multidrug resistance, (9) generates nonselective phenotypes such as metastasis (no benefit at native site) and “immortality” (not necessary for tumorigenesis), and (10) does not contain carcinogenic mutations. We propose, instead, that cancer is a chromosomal disease. Accordingly carcinogenesis is initiated by random aneuploidies, which are induced by carcinogens or spontaneously. Since aneuploidy unbalances 1000s of genes, it corrupts teams of proteins that segregate, synthesize and repair chromosomes. Aneuploidy is therefore a steady source of chromosomal variations from which, in classical Darwinian terms, selection encourages the evolution and malignant progression of cancer cells. The rates of specific chromosomal variations can exceed conventional mutations by 4–11 orders of magnitude, depending on the degrees of aneuploidy. Based on their chromosomal constitution cancer cells are new cell “species” with specific aneusomies, but unstable karyotypes. The cancer-specific aneusomies generate complex, malignant phenotypes through the abnormal dosages of 1000s of genes, just as trisomy 21 generates Down syndrome. In sum, cancer is caused by chromosomal disorganization, which increases karyotypic entropy. Thus, cancer is a chromosomal rather than a genetic disease. The chromosomal theory explains (1) non-heritable cancer because aneuploidy is not heritable, (2) non-mutagenic carcinogens as aneuploidogens, (3) long neoplastic latencies by the low probability of evolving new species, (4) nonselective phenotypes via genes hitchhiking with selective chromosomes, and (5) immortality because, through their cellular heterogeneity, cancers survive negative mutations and cytotoxic drugs via resistant subspecies.
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Maan, S. S. "Natural or induced nucleocytoplasmic heterogeneity in Triticum longissimum." Genome 39, no. 1 (1996): 71–76. http://dx.doi.org/10.1139/g96-010.
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Alien cytoplasms produce a variety of phenotypes in durum wheat (Triticum turgidum) and common wheat (Triticum aestivum) cultivars, which indicate the prevalence of cytoplasmic variability in the subtribe Triticinae. Intraspecific cytoplasmic differences have been demonstrated between the subspecies of Triticum speltoides, Triticum dichasians, and Triticum comosum. In this study, durum wheat lines with cytoplasm from two accessions, B and C, of Triticum longissimum were compared, and meiotic chromosome pairing between the group 4 homoeologues from the same two accessions was examined in common wheat. First, monosomic addition or monosomic substitution lines of common wheat with cytoplasm and one chromosome (designated B) from accession B were crossed with those having cytoplasm and a chromosome designated C-1 or C-2 from accession C. In each substitution line, an alien chromosome substituted for a group 4 homoeologue. Each alien chromosome had a "selfish" (Sf) gene, which remained fixed in the wheat nucleus. The F1s had greatly reduced meiotic pairing between chromosomes B and C-1 and B and C-2, which indicated greatly reduced homology between the group 4 homoeologues from the two accessions. Second, by using Triticum timopheevii as a bridging species, chromosome B in a common wheat line was eliminated and an euploid durum line with cytoplasm from accession B was obtained. This line was fertile. In contrast, a similarly produced durum line with cytoplasm from accession C was male sterile and retained a species cytoplasm specific (scs) nuclear gene from T. timopheevii. In conclusion, nuclear and cytoplasmic heterogeneity pre-existed between accessions B and C and they represent varieties or incipient subspecies in T. longissimum. Alternatively, the Sf genes produced chromosomal heterogeneity and mutated cytoplasmic genes from one or both accessions. Key words : meiotic drive, selfish gene (Sf), gametocidal gene (Gc), Triticum, Aegilops.
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Sánchez, Silvia, Benilde García-de-Teresa, Marco A. Mejía-Barrera, et al. "High Burden of Non-Clonal Chromosome Aberrations Before Onset of Detectable Neoplasia in Fanconi Anemia Bone Marrow." Cancers 17, no. 11 (2025): 1805. https://doi.org/10.3390/cancers17111805.
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Background/objectives: Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosome instability and predisposition to develop myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). Clonal chromosome aberrations (CCAs) in chromosomes 1, 3, and 7 frequently appear in the bone marrow (BM) of patients with FA and are associated with MDS/AML progression. Given the underlying DNA repair defect that characterizes FA, non-clonal chromosomal abnormalities (NCCAs) are expected to be common events in the FA BM; in this study, we investigated the presence and significance of NCCA and CCA in the bone marrow (BM) of patients with FA. Methods: Here, we transversally examined the BM karyotypes of 43 non-transplanted patients with FA, 41 with non-clinically detectable hematologic neoplasia and two with diagnosed MDS. We searched for the presence of NCCAs, complex karyotypes (CKs), and CCAs as well as their association with the natural history of the disease, including age, degree of BM failure, and neoplastic transformation. Results: NCCAs were observed in the metaphase spreads of 41/43 FA patients; CKs were observed in 25/43 patients; CCAs were found in 15/43 patients; CCAs involving chromosomes 1, 3 and/or 7 were found in four patients; and other autosomes were found in the remaining 11 patients. Overall, we observed a baseline large karyotypic heterogeneity in the BM of FA patients, demonstrated by the ubiquitous presence of NCCA; such karyotypic heterogeneity precedes the eventual emergence of CKs and selection of cells carrying fitness-improving CCAs. Finally, CCAs involving chromosomes 1, 3 and 7, well-known drivers of hematological malignancy in FA, become established. Overall, we observed that the frequency of NCCAs and CCAs increased with age, even though a significant correlation was not found. Conclusions: These observations fit the model of evolution towards cancer that comprises a first phase of macroevolution represented by NCCAs and karyotypic heterogeneity, followed by the establishment of clones with CCAs, leading to microevolution and cancer. NCCAs are the most frequent chromosomal alterations in the bone marrow of patients with AF and constitute a genome with extensive karyotypic heterogeneity that evolves into clones with more complex genomes and can eventually progress to cancer.
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Havelange, Violaine, Geneviève Ameye, Evelyne Callet-Bauchu, et al. "Multicolor Fluorescence In Situ Hybridization (M-FISH) in Highly Aggressive B-Cell Lymphomas with 8q24/MYC Involvement Revealed the Heterogeneity of 13q Abnormalities with Unexpected Partial Gains." Blood 108, no. 11 (2006): 2068. http://dx.doi.org/10.1182/blood.v108.11.2068.2068.
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Abstract Chromosomal translocations involving the MYC oncogene (8q24) are known to occur in Burkitt lymphomas/leukemias (BL) but also in 5–30% of diffuse large B-cell lymphomas which are usually highly aggressive (8q24 DLBCL). Two recent conventional cytogenetics (CC) studies showed that secondary chromosomal abnormalities have a negative prognostic impact, especially13q abnormalities (frequently described as a deletion and usually associated with a complex karyotype, i.e. > 3 chromosomal alterations), mainly in childhood mature B-cell lymphomas, and in a less extent 7q, 3q, 22q and chromosome 17. M-FISH was applied to 120 (74% adults and 26% children) high grade B-cell non-Hodgkin lymphomas (86% BL, 14% 8q24 DLBCL) carrying MYC rearrangement and complex karyotype and/or 13q abnormality in order to find recurrent and/or cryptic chromosomal alterations. Abnormal metaphases were available in 96 (80%) cases. We described ‘new’ (not seen in CC) chromosomal rearrangements in 50 (52%) cases, refined those seen by CC in 28 (29%) cases and confirmed CC abnormalities in 18 (19%) cases. M-FISH allowed to characterize 55 structural 13q abnormalities in 42 patients (21 ‘new’ alterations): 24 der(13q) leading to partial del(13q) and partial gain of different partner chromosomes [mainly 1q or 7q], 15 del(13q) [of 2 minimal regions : q14 & q31q34], 13 gains (only 2 seen by CC) and 3 balanced translocations. Combined results of CC and M-FISH showed that the most frequent abnormalities among patients with complex karyotype involved 1q, 7q, Xq, 3q, 18q, 6q, 17p and chromosome 22 (excluding 8q24 translocations). 79 1q abnormalities were detected in 54 patients (26 % ‘new’): mostly gains (minimal amplified region: q22q31) due to unbalanced translocations with chromosomes 13, 22, 7 (59%) or duplications (25%). 55 partial 7q gains were observed in 42 patients (22% ‘new’), mostly +7 or unbalanced translocations with 13q, 6q or 1q. The other most common abnormalities were: t(14;18) in 8q24 DLBCL, del(6q), der(3q) with various partners leading to partial loss of 3q, monosomy 17 or del(17p) and numerical changes of chromosomes 22 (monosomy) and X. In conclusion, this study confirms the contribution of M-FISH in refining CC results in highly aggressive 8q24 B-cell lymphomas: ‘new’ rearrangements were identified especially in 1q (leading to partial 1q gains), 18q, 6q (leading to partial 6q deletions), 13q ; partial 13q gains were underestimated by CC and both 13q deletions and gains were more heterogeneous than expected. We are characterizing these prognostic additional chromosomal abnormalities with SNP-CHIPS 50K array (Affymetrix) to look for candidate genes and/or cellular pathways involved in Burkitt lymphomagenesis in cooperation with oncogenic effect of MYC. °on behalf of the GFCH (Groupe Francophone de Cytogénétique Hématologique) and the BCG-Ho (Belgian Cytogenetic Group of Hematology and Oncology).
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Sun, Xiaochao, Bin Yang, and Qunye Zhang. "Analysis of Inter-Chromosomal Distribution of Disease-Related Genes in Human Genome." Current Protein & Peptide Science 21, no. 11 (2020): 1068–77. http://dx.doi.org/10.2174/1389203721666200426233158.
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: Many studies have shown that the spatial distribution of genes within a single chromosome exhibits distinct patterns. However, little is known about the characteristics of inter-chromosomal distribution of genes (including protein-coding genes, processed transcripts and pseudogenes) in different genomes. In this study, we explored these issues using the available genomic data of both human and model organisms. Moreover, we also analyzed the distribution pattern of protein-coding genes that have been associated with 14 common diseases and the insert/deletion mutations and single nucleotide polymorphisms detected by whole genome sequencing in an acute promyelocyte leukemia patient. We obtained the following novel findings. Firstly, inter-chromosomal distribution of genes displays a nonstochastic pattern and the gene densities in different chromosomes are heterogeneous. This kind of heterogeneity is observed in genomes of both lower and higher species. Secondly, protein-coding genes involved in certain biological processes tend to be enriched in one or a few chromosomes. Our findings have added new insights into our understanding of the spatial distribution of genome and disease- related genes across chromosomes. These results could be useful in improving the efficiency of disease-associated gene screening studies by targeting specific chromosomes.
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Prada-Luengo, Iñigo, Henrik D. Møller, Rasmus A. Henriksen, et al. "Replicative aging is associated with loss of genetic heterogeneity from extrachromosomal circular DNA in Saccharomyces cerevisiae." Nucleic Acids Research 48, no. 14 (2020): 7883–98. http://dx.doi.org/10.1093/nar/gkaa545.
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Abstract Circular DNA can arise from all parts of eukaryotic chromosomes. In yeast, circular ribosomal DNA (rDNA) accumulates dramatically as cells age, however little is known about the accumulation of other chromosome-derived circles or the contribution of such circles to genetic variation in aged cells. We profiled circular DNA in Saccharomyces cerevisiae populations sampled when young and after extensive aging. Young cells possessed highly diverse circular DNA populations but 94% of the circular DNA were lost after ∼15 divisions, whereas rDNA circles underwent massive accumulation to &gt;95% of circular DNA. Circles present in both young and old cells were characterized by replication origins including circles from unique regions of the genome and repetitive regions: rDNA and telomeric Y’ regions. We further observed that circles can have flexible inheritance patterns: [HXT6/7circle] normally segregates to mother cells but in low glucose is present in up to 50% of cells, the majority of which must have inherited this circle from their mother. Interestingly, [HXT6/7circle] cells are eventually replaced by cells carrying stable chromosomal HXT6 HXT6/7 HXT7 amplifications, suggesting circular DNAs are intermediates in chromosomal amplifications. In conclusion, the heterogeneity of circular DNA offers flexibility in adaptation, but this heterogeneity is remarkably diminished with age.
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Luo, Xiao-Yu, Tang-Jie Nie, Heng Liu, et al. "Karyotype and genome size variation in Delphinium subg. Anthriscifolium (Ranunculaceae)." PhytoKeys 234 (October 18, 2023): 145–65. http://dx.doi.org/10.3897/phytokeys.234.108841.
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Five taxa of Delphinium subg. Anthriscifolium have been karyologically studied through chromosome counting, chromosomal measurement, and karyotype symmetry. Each taxon that we investigated has a basic chromosome number of x = 8, D. anthriscifolium var. savatieri, D. anthriscifolium var. majus, D. ecalcaratum, and D. callichromum were diploid with 2n = 16, while D. anthriscifolium var. anthriscifolium was tetraploid with 2n = 32. Monoploid chromosome sets of the investigated diploid taxa contained 1 metacentric chromosome, 3 submetacentric chromosomes, and 4 subtelocentric chromosomes. Higher interchromosomal asymmetry (CVCL) was present in D. ecalcaratum and D. callichromum than in other taxa. The highest levels of intrachromosomal asymmetry (MCA) and heterogeneity in centromere position (CVCI) were found in D. anthriscifolium var. majus. Diploid and tetraploid genome sizes varied by 3.02–3.92 pg and 6.04–6.60 pg, respectively. Karyotype and genome size of D. anthriscifolium var. savatieri, D. anthriscifolium var. majus, D. callichromum, and D. ecalcaratum were reported for the first time. Finally, based on cytological and morphological data, the classification of Delphinium anthriscifolium was revised.
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Tapia-Pastrana, Fernando, Alfonso Delgado-Salinas, and Javier Caballero. "Patterns of chromosomal variation in Mexican species of Aeschynomene (Fabaceae, Papilionoideae) and their evolutionary and taxonomic implications." Comparative Cytogenetics 14, no. 1 (2020): 157–82. http://dx.doi.org/10.3897/compcytogen.v14i1.47264.
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A cytogenetic analysis of sixteen taxa of the genus Aeschynomene Linnaeus, 1753, which includes species belonging to both subgenera Aeschynomene (Léonard, 1954) and Ochopodium (Vogel, 1838) J. Léonard, 1954, was performed. All studied species had the same chromosome number (2n = 20) but exhibited karyotype diversity originating in different combinations of metacentric, submetacentric and subtelocentric chromosomes, chromosome size and number of SAT chromosomes. The plasticity of the genomes included the observation in a taxon belonging to the subgenus Aeschynomene of an isolated spherical structure similar in appearance to the extra chromosomal circular DNA observed in other plant genera. By superimposing the karyotypes in a recent phylogenetic tree, a correspondence between morphology, phylogeny and cytogenetic characteristics of the taxa included in the subgenus Aeschynomene is observed. Unlike subgenus Aeschynomene, the species of Ochopodium exhibit notable karyotype heterogeneity. However the limited cytogenetic information recorded prevents us from supporting the proposal of their taxonomic separation and raise it to the genus category. It is shown that karyotype information is useful in the taxonomic delimitation of Aeschynomene and that the diversity in the diploid level preceded the hybridization/polyploidization demonstrated in the genus. The systematic implications of our results and their value can be extended to other Dalbergieae genera as knowledge about the chromosomal structure and its evolution increases.
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Tapia-Pastrana, Fernando, Alfonso Delgado-Salinas, and Javier Caballero. "Patterns of chromosomal variation in Mexican species of Aeschynomene (Fabaceae, Papilionoideae) and their evolutionary and taxonomic implications." Comparative Cytogenetics 14, no. (1) (2020): 157–82. https://doi.org/10.3897/CompCytogen.v14i1.47264.
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A cytogenetic analysis of sixteen taxa of the genus Aeschynomene Linnaeus, 1753, which includes species belonging to both subgenera Aeschynomene (Léonard, 1954) and Ochopodium (Vogel, 1838) J. Léonard, 1954, was performed. All studied species had the same chromosome number (2n = 20) but exhibited karyotype diversity originating in different combinations of metacentric, submetacentric and subtelocentric chromosomes, chromosome size and number of SAT chromosomes. The plasticity of the genomes included the observation in a taxon belonging to the subgenus Aeschynomene of an isolated spherical structure similar in appearance to the extra chromosomal circular DNA observed in other plant genera. By superimposing the karyotypes in a recent phylogenetic tree, a correspondence between morphology, phylogeny and cytogenetic characteristics of the taxa included in the subgenus Aeschynomene is observed. Unlike subgenus Aeschynomene, the species of Ochopodium exhibit notable karyotype heterogeneity. However the limited cytogenetic information recorded prevents us from supporting the proposal of their taxonomic separation and raise it to the genus category. It is shown that karyotype information is useful in the taxonomic delimitation of Aeschynomene and that the diversity in the diploid level preceded the hybridization/polyploidization demonstrated in the genus. The systematic implications of our results and their value can be extended to other Dalbergieae genera as knowledge about the chromosomal structure and its evolution increases.
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XIAO, Y. "Heterogeneity of Chinese hamster X chromosomes in X-ray-induced chromosomal aberrations." International Journal of Radiation Biology 75, no. 4 (1999): 419–27. http://dx.doi.org/10.1080/095530099140339.
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Tanksley, S. D., M. W. Ganal, J. P. Prince, et al. "High density molecular linkage maps of the tomato and potato genomes." Genetics 132, no. 4 (1992): 1141–60. http://dx.doi.org/10.1093/genetics/132.4.1141.
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Abstract High density molecular linkage maps, comprised of more than 1000 markers with an average spacing between markers of approximately 1.2 cM (ca. 900 kb), have been constructed for the tomato and potato genomes. As the two maps are based on a common set of probes, it was possible to determine, with a high degree of precision, the breakpoints corresponding to 5 chromosomal inversions that differentiate the tomato and potato genomes. All of the inversions appear to have resulted from single breakpoints at or near the centromeres of the affected chromosomes, the result being the inversion of entire chromosome arms. While the crossing over rate among chromosomes appears to be uniformly distributed with respect to chromosome size, there is tremendous heterogeneity of crossing over within chromosomes. Regions of the map corresponding to centromeres and centromeric heterochromatin, and in some instances telomeres, experience up to 10-fold less recombination than other areas of the genome. Overall, 28% of the mapped loci reside in areas of putatively suppressed recombination. This includes loci corresponding to both random, single copy genomic clones and transcribed genes (detected with cDNA probes). The extreme heterogeneity of crossing over within chromosomes has both practical and evolutionary implications. Currently tomato and potato are among the most thoroughly mapped eukaryotic species and the availability of high density molecular linkage maps should facilitate chromosome walking, quantitative trait mapping, marker-assisted breeding and evolutionary studies in these two important and well studied crop species.
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Cunningham, Chelsea E., Mackenzie J. MacAuley, Frederick S. Vizeacoumar, Omar Abuhussein, Andrew Freywald, and Franco J. Vizeacoumar. "The CINs of Polo-Like Kinase 1 in Cancer." Cancers 12, no. 10 (2020): 2953. http://dx.doi.org/10.3390/cancers12102953.
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Polo-like kinase 1 (PLK1) is overexpressed near ubiquitously across all cancer types and dysregulation of this enzyme is closely tied to increased chromosomal instability and tumor heterogeneity. PLK1 is a mitotic kinase with a critical role in maintaining chromosomal integrity through its function in processes ranging from the mitotic checkpoint, centrosome biogenesis, bipolar spindle formation, chromosome segregation, DNA replication licensing, DNA damage repair, and cytokinesis. The relation between dysregulated PLK1 and chromosomal instability (CIN) makes it an attractive target for cancer therapy. However, clinical trials with PLK1 inhibitors as cancer drugs have generally displayed poor responses or adverse side-effects. This is in part because targeting CIN regulators, including PLK1, can elevate CIN to lethal levels in normal cells, affecting normal physiology. Nevertheless, aiming at related genetic interactions, such as synthetic dosage lethal (SDL) interactions of PLK1 instead of PLK1 itself, can help to avoid the detrimental side effects associated with increased levels of CIN. Since PLK1 overexpression contributes to tumor heterogeneity, targeting SDL interactions may also provide an effective strategy to suppressing this malignant phenotype in a personalized fashion.
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Jäger, Roland, Damla Olcaydu, Tiina Berg, Bettina Gisslinger, Heinz Gisslinger, and Robert Kralovics. "Chromosomal Instability Causes Genetic and Clonal Heterogeneity in Myeloproliferative Neoplasms and Is Not Restricted to JAK2-V617F Positive Cells." Blood 112, no. 11 (2008): 178. http://dx.doi.org/10.1182/blood.v112.11.178.178.
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Abstract A number of oncogenic mutations have been identified in myeloproliferative neoplasms (MPN) in the past few years. Among these JAK2-V617F is most frequent, followed by mutations of the thrombopoietin receptor MPL and JAK2 exon 12. In addition, cytogenetic lesions occur frequently in MPN detected either at diagnosis or later in the course of the disease. To explore the genetic aberrations present in MPN patients, we performed microarray genotyping using Affymetrix SNP 6.0 arrays in a series of 71 MPN patients with variable presence of JAK2 and MPL mutations. More than half of the analyzed patients exhibited loss of heterozygosity (LOH) in at least one chromosomal region. Complex karyotypes with two and more regions with LOH were detected in 18 patients. Uniparental disomy (UPD) on chromosomes 9p, 1p, 11q, 14q and 17q represented the largest proportion of LOH detected followed by deletions on chromosome 13q, 20q, and 12p. All patients with UPD on chromosome 1p were homozygous for the MPL-W515L mutation. We observed frequent aberrations of chromosome 7 including monosomy, deletions on 7p and 7q, and UPD of 7q. Using microsatellite PCR, we validated the microarray findings and further determined the frequency of these aberrations in a total of 367 MPN patients. Multiple occurrences of individual chromosomal lesions allowed us to define the minimal genomic regions involved in deletions or UPDs. The sizes of the common deleted regions (CDRs) were variable ranging from 9 mega base pairs (Mb) to 0.5 Mb. The CDR on chromosome 7p included only the IKZF1 and FIGNL1 genes previously shown to associate with leukemic transformation. To determine the clonal composition of the hematopoietic progenitor pool of patients with complex karyotypes we genotyped individual BFU-E and CFU-GM colonies in a series of 27 patients. We observed a remarkable clonal heterogeneity at the progenitor cell level. Using four clonal markers we defined 9 different types of clonal structures. In a set of patients, JAK2-V617F or MPL-W515L mutations occurred before the acquisition of chromosomal deletions. Other patients acquired deletions before the acquisition of JAK2-V617F. In summary, our results show that somatic mutations in MPN are not acquired in a predetermined order as seen in other malignancies, but occur randomly. The chromosomal instability in MPN is not caused by JAK2-V617F exclusively, since many patients show aberrations outside of the JAK2-V617F positive clone. Heterogeneity of somatic mutations in MPN leads to high clonal variability within the progenitor pool potentially affecting therapeutic outcome. Thus, targeting JAK2-V617F alone may not lead to restoration of polyclonal hematopoiesis. An individualized therapeutic approach and/or combination therapy might be necessary to achieve clonal remission in MPN.
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Bassett, Anne S. "Chromosomal Aberrations and Schizophrenia." British Journal of Psychiatry 161, no. 3 (1992): 323–34. http://dx.doi.org/10.1192/bjp.161.3.323.
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Chromosomal aberrations associated with schizophrenic disorders may suggest regions in which to focus a search for genes predisposing to schizophrenia by a linkage strategy. As for other genetic illnesses, chromosomal abnormalities may also provide useful tools for subsequent physical mapping, fine localisation, and isolation of important susceptibility genes. Identification of several chromosomal aberrations may be especially important, given the unknown pathophysiology, the paucity of known brain genes, and the probable genetic heterogeneity of schizophrenia and manic-depression. However, because psychiatric disorders are common and inherited in a complex manner, researchers must use caution when drawing inferences about associations with chromosomal aberrations. Reported abnormalities involving autosomes (chromosomes 1–22) associated with psychotic disorders are reviewed. Their relevance to linkage studies localising genes for schizophrenia was estimated by standardised criteria for specificity, diagnosis, family history, and overall weight of evidence. Four ‘possibly relevant’ chromosomal regions were identified: 5q, 11q, 18q, and 19p. This paper outlines strategies for future studies to detect new chromosomal aberrations associated with major psychotic disorders that may be relevant to isolating the genes for schizophrenia.
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Pandey, Himani, Jyoti Sharma, Sourabh Kumar, et al. "Chromosomal Microarray Analysis in Spina Bifida: Genetic Heterogeneity and Its Clinical Implications." Journal of Indian Association of Pediatric Surgeons 30, no. 3 (2025): 290–95. https://doi.org/10.4103/jiaps.jiaps_217_24.
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ABSTRACT Background: The etiology of spina bifida is multifactorial; the phenotype is the end result of both genetic and environmental influences. While whole exome sequencing has identified several pathogenic variants in Indian cohorts, the role of chromosomal imbalances and long contiguous stretches of homozygosity (LCSHs) remains largely unexplored in this population. Chromosomal microarray analysis (CMA) is an important tool that provides insights into such genetic aberrations, making it significant for evaluating patients with spina bifida. Objective: To identify LCSHs and chromosomal imbalances in three spina bifida patients through CMA analysis as a pilot investigation. Materials and Methods: Genomic DNA was isolated from three spina bifida patients (P1: 10-year-old female, P2: 1-year-old male, and P3: 2.8-year-old male) and subjected to CMA using the Affymetrix 750K high-density array platform. The submicroscopic chromosomal imbalances and LCSHs were cross-referenced with public databases (Database of Genomic Variants, ClinVar, and OMIM) to evaluate their clinical significance. Functional annotations of the affected genes were performed to understand their role in neural tube development. Results: CMA revealed significant LCSH on chromosomes 2, 3, and 7 involving the genes SOX11, WNT7A, FZD9, SEMA3A, and VHL, all of which are involved in neural tube closure. Mosaic Klinefelter syndrome (25.9% mosaicism) was identified in the second patient while the third patient had a normal genetic profile. The detection of significant genetic variations in two of three cases underscores the potential utility of CMA in spina bifida patients. Conclusions: This study has generated valuable insights into the complex genetic landscape underlying the multifactorial etiopathogenesis of spina bifida. The findings not only underscore the importance of an integrated approach but also support the cause of a platform for large-scale investigations in the Indian population.
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Mokhtar, M. M. "Chromosomal aberrations in children with suspected genetic disorders." Eastern Mediterranean Health Journal 3, no. 1 (1997): 114–22. http://dx.doi.org/10.26719/1997.3.1.114.
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Karyotyping was done in 137 children suspected of having chromosomal abnormalities such as genetically uncertain syndromes, multiple congenital anomalies, short stature, dysmorphic features, unclassified mental retardation and Down syndrome. A total of 53 [38.7%] had an abnormal karyotype:trisomy 21 [36;26.3%], trisomy 18 [3;2.2%], trisomy 13 [1;0.7%], partial autosomal aneuploidy [5;3.6%], pericentric inversion of chromosome 9 [2;1.5%], marker chromosome [2;1.5%] and sex chromosome aberrations [4;2.9%]. All of them showed phenotypic-cytogenetic heterogeneity. These findings suggest that cytogenetic analysis is useful in the investigation of children with genetic disorders of unknown origin to confirm clinical diagnosis and to allow for proper genetic counseling
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Lemos Costa, Alice, Cassiane Furlan Lopes, Marcelo Santos de Souza, et al. "Comparative cytogenetics in three species of Wood-Warblers (Aves: Passeriformes: Parulidae) reveal divergent banding patterns and chromatic heterogeneity for the W chromosome." Caryologia 74, no. 1 (2021): 43–51. http://dx.doi.org/10.36253/caryologia-839.
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Chromosomal rearrangements are an important process in the evolution of species. It is assumed that these rearrangements occur near repetitive sequences and heterochromatic regions. Avian karyotypes have diverse chromosomal band patterns and have been used as the parameters for phylogenetic studies. Although the group has a high diversity of species, no more than 12% has been analyzed cytogenetically, and the Parulidae family are extremely underrepresented in these studies. The aim of this study was to detect independent or simultaneous chromosomal rearrangements, and also to analyze chromosomal banding convergences and divergences of three Wood-Warblers species (Myiothlypis leucoblephara, Basileuterus culicivorus, and Setophaga pitiayumi). Our CBG-band results reveal an unusual W sex chromosome in the three studied species, containing a telomeric euchromatic region. The GTG and RBG bands identify specific regions in the macrochromosomes involved in the rearrangements. Cytogenetic data confirm the identification of speciation processes at the karyotypic of this group.
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Aksenova, Anna Yurevna, A. S. Zhuk, E. I. Stepchenkova, and Sergei Vasilevich Gritsaev. "Stratification of Patients with Multiple Myeloma: State-of-the-Art and Prospects." Clinical oncohematology 15, no. 3 (2022): 259–70. http://dx.doi.org/10.21320/2500-2139-2022-15-3-259-270.
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In recent years, there has been a substantial progress in improving progression-free survival (PFS) and quality of life of multiple myeloma (MM) patients. This has become possible through implementation of novel drugs into clinical practice which were developed on the basis of multiomic molecular genetic studies in MM. The results of these studies also enabled to assess genetic heterogeneity of tumor cells in MM. That allowed to identify types and prevalence of single-nucleotide variations, structural chromosomal aberrations, and abnormal copy numbers of chromosomes in the genome of malignant plasma cells. It was shown that MM patients can have quite different spectra of detected genetic defects in the tumor. High genetic disease heterogeneity is one of the major causes of differences in drug efficacy and PFS. The present review comprehensively discusses the value of some chromosomal aberrations in risk stratification of MM patients. It describes the most prevalent aberrations, also those associated with high and low risk of early MM progression which have already been included in different international prognostic scores. Besides, the additional aberrations were determined which are potentially applicable in clinical practice. Special attention was paid to risk assessment in case a number of different chromosome rearrangements are identified in a patient. The review outlines challenges and prospects of dealing with the information on chromosome rearrangements in choosing the most optimal treatment strategy and assessing of its efficacy. In this context, emphasis is laid on integrating genetic data and such clinical parameters as age, comorbidity, renal failure, bone lesions, indications for autologous hematopoietic stem cell transplantation, etc.
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Tan, Zhihao, Yong Jie Andrew Chan, Ying Jie Karen Chua, et al. "Environmental stresses induce karyotypic instability in colorectal cancer cells." Molecular Biology of the Cell 30, no. 1 (2019): 42–55. http://dx.doi.org/10.1091/mbc.e18-10-0626.
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Understanding how cells acquire genetic mutations is a fundamental biological question with implications for many different areas of biomedical research, ranging from tumor evolution to drug resistance. While karyotypic heterogeneity is a hallmark of cancer cells, few mutations causing chromosome instability have been identified in cancer genomes, suggesting a nongenetic origin of this phenomenon. We found that in vitro exposure of karyotypically stable human colorectal cancer cell lines to environmental stress conditions triggered a wide variety of chromosomal changes and karyotypic heterogeneity. At the molecular level, hyperthermia induced polyploidization by perturbing centrosome function, preventing chromosome segregation, and attenuating the spindle assembly checkpoint. The combination of these effects resulted in mitotic exit without chromosome segregation. Finally, heat-induced tetraploid cells were on the average more resistant to chemotherapeutic agents. Our studies suggest that environmental perturbations promote karyotypic heterogeneity and could contribute to the emergence of drug resistance.
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Tukiainen, Taru, Alexandra-Chloé Villani, Angela Yen, et al. "Landscape of X chromosome inactivation across human tissues." Nature 550, no. 7675 (2017): 244–48. http://dx.doi.org/10.1038/nature24265.
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Abstract X chromosome inactivation (XCI) silences transcription from one of the two X chromosomes in female mammalian cells to balance expression dosage between XX females and XY males. XCI is, however, incomplete in humans: up to one-third of X-chromosomal genes are expressed from both the active and inactive X chromosomes (Xa and Xi, respectively) in female cells, with the degree of ‘escape’ from inactivation varying between genes and individuals1,2. The extent to which XCI is shared between cells and tissues remains poorly characterized3,4, as does the degree to which incomplete XCI manifests as detectable sex differences in gene expression5 and phenotypic traits6. Here we describe a systematic survey of XCI, integrating over 5,500 transcriptomes from 449 individuals spanning 29 tissues from GTEx (v6p release) and 940 single-cell transcriptomes, combined with genomic sequence data. We show that XCI at 683 X-chromosomal genes is generally uniform across human tissues, but identify examples of heterogeneity between tissues, individuals and cells. We show that incomplete XCI affects at least 23% of X-chromosomal genes, identify seven genes that escape XCI with support from multiple lines of evidence and demonstrate that escape from XCI results in sex biases in gene expression, establishing incomplete XCI as a mechanism that is likely to introduce phenotypic diversity6,7. Overall, this updated catalogue of XCI across human tissues helps to increase our understanding of the extent and impact of the incompleteness in the maintenance of XCI.
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Jain, Saket, Husam Babikir, karin Shamardani, Aaron Diaz, and Manish Aghi. "OTEH-11. Single Cell RNA Sequencing to identify cellular heterogeneity with in Pituitary Adenomas." Neuro-Oncology Advances 3, Supplement_2 (2021): ii12—ii13. http://dx.doi.org/10.1093/noajnl/vdab070.050.
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Abstract Pituitary adenomas (PA) are one of the most common primary brain tumors and comprise approximately 15% of brain neoplasms. Most PA are histologically benign, but can cause significant morbidity. Previous studies utilized whole genome and exome sequencing to identify a few somatic variants, but no recurrent mutations were observed. Further studies are warranted to identify driver mutations occurring at low frequencies. We used single-cell RNA sequencing (10X Genomics) to investigate cellular heterogeneity in 12 non-functioning pituitary adenomas. Our analysis identified discrete clusters of cells associated with specific functional pathways. One of these clusters corresponded to cells expressing genes related to metabolic pathways, primarily lipid metabolism. Another cluster consistent amongst the three patients comprised cells involved in antigen presentation and processing. In addition, the copy number variation analysis highlighted distinct chromosomal alterations within our samples. Interestingly, we were able to identify clonal variations within each tumor based on chromosomal aberrations. For example, in our first patient we observed a gain of chromosome 19 and loss of chromosome 2. Our analysis showed three different clonal populations within this tumor. All three populations harbored the loss of chromosome 2, one population exhibited gain of chromosome 19, while a third population exhibited loss of chromosome 19. These early results indicate the loss of chromosome 2 as an early event in tumorigenesis and gain/loss of chromosome 19 as late events. We are currently in a process of identifying somatic variations within these tumors by variant calling. Currently we are expanding our analysis to 20 non-functional PA. Mapping the single-cell gene expression profiles with mutational phylogeny will reveal the differences in clonal evolution within the tumor subtypes. This study will help us define the molecular fingerprint of pituitary adenomas and provide insights which could be utilized in the clinic for better management of these tumors.
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Ganzel, Chezi, Yishai Ofran, Bayan Alyan, et al. "Templated Insertion Mediates Generation of p190 BCR/ABL Facilitating CML Heterogeneity Uniquely Detected By Optical Genome Mapping." Blood 144, Supplement 1 (2024): 6577. https://doi.org/10.1182/blood-2024-209728.
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Philadelphia chromosome (Ph) a hallmark of chronic myeloid leukemia (CML), is a result of reciprocal translocation t(9;22) generating aberrant persistently activate oncogenic tyrosine- kinase (BCR/ABL1) facilitating leukemogenesis. It was demonstrated that simultaneous breakages of two different chromosomes within BCR and ABL1 loci, serve as an oncogenic initiation of Ph+ leukemia. Thus, recurrency of Ph and other translocations in hematopoietic stem cells indicates that chromosomal instability (CIN) is leading pathogenetics of leukemogenesis. Surprisingly, despite established diagnostic methods and knowledge on CML, use of Optical Genome Mapping (OGM) identified novel pathogenetic landscape of chromosomal aberrations and generation of BCR/ABL1 p190 fusion gene without formation of Ph chromosome. We found that dominant characteristics of CIN in these leukemia cells is increase of clustered aberrations at distinct breakpoints throughout a genome with proximity to microhomology-enriched segments. We detected significant accumulation of double-strand breaks (DSBs) at near-overlapping origins of replications. OGM and chromosomal analyses strongly correlate with induced distinct expression profile and activation of microhomology-mediated break induce repair (MMBIR). MMBIR utilizes microhomology for DSB repair, producing templated insertions that promote complex genomic rearrangements detected in cancer including chromosomal illegitimate recombination, integrations and fusions. Despite growing evidence on accumulation of de novo templated insertions in several cancer types, the underlying molecular and genomic mechanisms, impact on carcinogenesis and heterogeneity, particularly in hematopoietic cells are poorly understood. Based on OGM, omics data mining and NGS, we developed sophisticated screening panels and molecular analyses to study BCR, ABL1, corresponding breakpoints loci, and near-overlapping microhomology-enriched elements, to identify and characterize this novel atypical p190 fusion gene. Our results indicate that in some CML patients', with unique CIN signature, induced mechanism of de novo templated insertions generating atypical p190 fusion gene instead of Ph chromosome formation. It's well established that different BCR/ABL1 transcripts correspond to distinct CML clinical phenotype. Furthermore, chronic, accelerated and blast phases of CML progression evaluated and measured by expression rate of each Ph+ BCR/ABL1 transcript variant, resulting in prediction of therapy response, and clinical outcomes. However, in few CML patients, standard assessments succeeded to detect fusion gene induced by templated insertion and monitor atypical transcripts. Thus, generally, standard tests were insufficient to assess expression rate of atypical p190 transcript initially and in MRD. Importantly, precise definition of the disease is challenging in patients with minimal CML. For example, preliminary screen detected templated insertions with atypical p190 BCR/ABL1 fusion genes in 6 patients. 3 patients were JAK2 V617F positive, while 2 subsequently treated for Essential Thrombocytosis. Third patient diagnosed and treated for p210 Ph+CML. In contrast, spontaneous recovery observed in other 3 patients, with allelic frequency of atypical p190 transcript lower than 0.035%. Thus, detection of minor clones with templated insertions, characterization of related abnormalities provide critical insights during early detection on clinical significance of atypical p190 transcript, necessity of further molecular testing and treatment evaluation. Hence, we developed robust molecular assay to measure atypical p190 transcripts to assist diagnosis and monitoring MRD. In contrast, ongoing study points on importance of MRD monitoring, detection CIN signatures, accumulation of templated insertions promoting transformation. In conclusion, our study indicates that distinct CIN signature orchestrates unique DNA repair landscape. Lack of precise molecular assessment, and genetic identification of seemingly similar oncogenes originated from atypical fusion gene, or Ph chromosome can be providing misleading diagnostics. Furthermore, our results suggest that increased heterogeneity observed among CML patients, reflect on clonal ability to repair DNA damage, preserve genome stability and function, affecting carcinogenesis.
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Dupuy, Berit Myhre, Margurethe Stenersen, Tim T. Lu, and Bjørnar Olaisen. "Geographical heterogeneity of Y-chromosomal lineages in Norway." Forensic Science International 164, no. 1 (2006): 10–19. http://dx.doi.org/10.1016/j.forsciint.2005.11.009.
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Frey, J., A. Haldimann, and J. Nicolet. "Chromosomal Heterogeneity of Various Mycoplasma hyopneumoniae Field Strains." International Journal of Systematic Bacteriology 42, no. 2 (1992): 275–80. http://dx.doi.org/10.1099/00207713-42-2-275.
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YE, F., F. LAIGRET, P. CARLE, and J. M. BOVE. "Chromosomal Heterogeneity among Various Strains of Spiroplasma citri." International Journal of Systematic Bacteriology 45, no. 4 (1995): 729–34. http://dx.doi.org/10.1099/00207713-45-4-729.
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Hemmer, Joerg, and Carmen Hauser. "Chromosomal Composition of Aneuploid Clones with Different DNA Contents in Head and Neck Squamous Cell Carcinomas as Determined by Combined Flow Cytometry and FluorescenceIn SituHybridization." Analytical Cellular Pathology 20, no. 4 (2000): 197–203. http://dx.doi.org/10.1155/2000/235942.
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Studies with DNA flow cytometry (FCM) have shown that DNA contents of aneuploid tumour clones vary in a wide range. The aim of this study was to analyse whether homologous chromosomal changes exist despite the individual differences that may be of general relevance for the development of gross aneuploidy in squamous cell carcinomas of the head and neck. Fluorescencein situhybridization (FISH) with 13 centromere‐specific DNA probes was applied to 3 diploid and 11 aneuploid tumours with DNA indices ranging between 0.8 and 2.2. Disomic and monosomic cell populations were prevalent findings in DNA‐diploid tumours. Polysomies were common in aneuploid tumours. Different degrees of aneusomy for identical chromosomes were recurrent features in aneuploid tumours. FISH signal heterogeneity was identified for all chromosomes. The mean number of aneusomic cell populations identified for DNA‐aneuploid tumours ranged between 1.6 for chromosome 17 and 3.1 for chromosome 3. Inconsistencies between FISH and FCM data may indicate that centromere‐specific DNA probes identify gains and losses of marker DNA due to complex karyotypic rearrangements rather than absolute changes in chromosome numbers. Overall, there was no evidence of the critical involvement of particular chromosomes in the development of different DNA contents.
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Cuéllar, T., J. Orellana, E. Belhassen, and J. L. Bella. "Chromosomal characterization and physical mapping of the 5S and the 18S-5.8S-25S ribosomal DNA in Helianthus argophyllus, with new data from Helianthus annuus." Genome 42, no. 1 (1999): 110–15. http://dx.doi.org/10.1139/g98-112.
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The characterization of the mitotic chromosomes of Helianthus argophyllus by means of Feulgen staining, Giemsa C-banding, and the usual DNA sequence-specific fluorochromes allows a chromosomal classification of this species, and shows that two kinds of heterochromatin co-exist equilocally in its chromosomes. One type is confined to the pericentromeric areas of all the chromosomes and the other is associated with the secondary constrictions of the satellite chromosomes. This species is evolutionarily very close to H. annuus with which it is involved in introgression breeding programs. Since these two species show no intra- or interspecific differences with the above treatments, we have used C-banding followed by DAPI, chromomycin A3 or Acridine Orange, and the fluorescent in situ hybridization (FISH) with 5S and 18S-25S ribosomal DNA probes to characterize further the chromosomes of both species in an attempt to find practically applicable chromosomal markers. Our results confirm the heterogeneity of the heterochromatin in these species and show that neither its distribution nor its response to distinct fluorochrome treatments allows better discrimination of the chromosomes within or between the species. On the other hand, the 18S-5.8S-25S rDNA arrays are located in the secondary constrictions of the satellited SM7, SM10, and ST13 pairs and the 5S-rDNA genes are interstitially placed on the short arm of the SM7 and SM11 chromosomes in both species. This permits these chromosomes to be distinguished and provides markers which may be helpful for further physical mapping of DNA sequences in these species.Key words: chromosome banding, sunflower cytogenetics, heterochromatin, ribosomal DNA mapping, FISH.