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Acta Medica Academica Apr 2019The aim of this review is to summarize the current knowledge of genomic information in multiple myeloma. Multiple myeloma is a genetically complex plasma cell neoplasm... (Review)
Review
The aim of this review is to summarize the current knowledge of genomic information in multiple myeloma. Multiple myeloma is a genetically complex plasma cell neoplasm that evolves from pre-malignant stages following genomic evolution leading to the proliferation of malignant plasma cells and the production of monoclonal immunoglobulin. The outcomes of patients with myeloma have dramatically improved over the past decade with the introduction of novel agents. Nevertheless, the disease is considered incurable and displays considerable heterogeneity in clinical presentation, course and survival. This heterogeneity can often be traced to cytogenetic abnormalities in the malignant clone. Accordingly, a large body of literature has examined the impact of genomics on myeloma and risk stratification based on cytogenetics has been adopted. In this review, we will focus on the cytogenetics of multiple myeloma and the prognostic significance as well as possible predictive implications. We will briefly review the existing methodologies relevant to myeloma but explore in greater depth the more novel molecular tools as applied to this disease. CONCLUSION: The field of genomics in multiple myeloma is rapidly evolving however more translational research is needed to accurately use genomic data as a tool of precision medicine.
Topics: Chromosome Aberrations; Cytogenetics; Genomics; Humans; Multiple Myeloma; Prognosis
PubMed: 31264433
DOI: 10.5644/ama2006-124.242 -
American Journal of Human Genetics Aug 2021Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard...
Chromosomal aberrations including structural variations (SVs) are a major cause of human genetic diseases. Their detection in clinical routine still relies on standard cytogenetics. Drawbacks of these tests are a very low resolution (karyotyping) and the inability to detect balanced SVs or indicate the genomic localization and orientation of duplicated segments or insertions (copy number variant [CNV] microarrays). Here, we investigated the ability of optical genome mapping (OGM) to detect known constitutional chromosomal aberrations. Ultra-high-molecular-weight DNA was isolated from 85 blood or cultured cells and processed via OGM. A de novo genome assembly was performed followed by structural variant and CNV calling and annotation, and results were compared to known aberrations from standard-of-care tests (karyotype, FISH, and/or CNV microarray). In total, we analyzed 99 chromosomal aberrations, including seven aneuploidies, 19 deletions, 20 duplications, 34 translocations, six inversions, two insertions, six isochromosomes, one ring chromosome, and four complex rearrangements. Several of these variants encompass complex regions of the human genome involved in repeat-mediated microdeletion/microduplication syndromes. High-resolution OGM reached 100% concordance compared to standard assays for all aberrations with non-centromeric breakpoints. This proof-of-principle study demonstrates the ability of OGM to detect nearly all types of chromosomal aberrations. We also suggest suited filtering strategies to prioritize clinically relevant aberrations and discuss future improvements. These results highlight the potential for OGM to provide a cost-effective and easy-to-use alternative that would allow comprehensive detection of chromosomal aberrations and structural variants, which could give rise to an era of "next-generation cytogenetics."
Topics: Chromosome Aberrations; Chromosome Disorders; Chromosome Mapping; Cytogenetic Analysis; DNA Copy Number Variations; Genome, Human; Humans; Karyotyping; Microarray Analysis
PubMed: 34237280
DOI: 10.1016/j.ajhg.2021.05.012 -
Cancer Genomics & Proteomics 2023Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six...
BACKGROUND/AIM
Angioleiomyoma is a benign tumor, occurs at any age, and arises most frequently in the lower extremities. Genetic information on angioleiomyomas is restricted to six reported abnormal karyotypes, losses in chromosome 22 and gains in Xq found by comparative genomic hybridization, and mutation analysis of notch receptor 2 (NOTCH2), NOTCH3, platelet-derived growth factor receptor beta (PDGFRB), and mediator complex subunit 12 (MED12) in a few tumors. Herein, we report the genetic findings in another three angioleiomyomas.
MATERIALS AND METHODS
The tumors were examined using G-banding and karyotyping, RNA sequencing, reverse transcription-polymerase chain reaction, Sanger sequencing, and expression analysis.
RESULTS
The first tumor carried a t(4;5)(p12;q32) translocation resulting in fusion of the cardiac mesoderm enhancer-associated non-coding RNA (CARMN in 5q32) with the TXK tyrosine kinase gene (TXK in 4p12) leading to overexpression of TXK. To our knowledge, this is the first time that a recurrent chromosome translocation and its resulting fusion gene have been described in angioleiomyomas. The second tumor carried a four-way translocation, t(X;3;4;16)(q22;p11;q11;p13) which fused the myosin heavy chain 11 gene (MYH11 in 16p13) with intergenic sequences from Xq22 that mapped a few kilobase pairs distal to the insulin receptor substrate 4 gene (IRS4), resulting in enhanced IRS4 expression. The third angioleiomyoma carried another rearrangement of chromosome band Xq22, t(X;9)(q22;q32), as the sole cytogenetic aberration, but no material was available for further molecular investigation.
CONCLUSION
Our data, together with previously reported abnormal karyotypes in angioleiomyomas, show the presence of two recurrent genetic pathways in this tumor type: The first is characterized by presence of the translocation t(4;5)(p12;q32), which generates a CARMN::TXK chimera. The second is recurrent rearrangement of Xq22 resulting in overexpression of IRS4.
Topics: Humans; Angiomyoma; Comparative Genomic Hybridization; Chromosome Aberrations; Translocation, Genetic; Transcription Factors; Abnormal Karyotype
PubMed: 37889065
DOI: 10.21873/cgp.20405 -
Genes Jan 2019Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90%... (Review)
Review
Anticancer regimens for Hodgkin lymphoma (HL) patients include highly genotoxic drugs that have been very successful in killing tumor cells and providing a 90% disease-free survival at five years. However, some of these treatments do not have a specific cell target, damaging both cancerous and normal cells. Thus, HL survivors have a high risk of developing new primary cancers, both hematologic and solid tumors, which have been related to treatment. Several studies have shown that after treatment, HL patients and survivors present persistent chromosomal instability, including nonclonal chromosomal aberrations. The frequency and type of chromosomal abnormalities appear to depend on the type of therapy and the cell type examined. For example, MOPP chemotherapy affects hematopoietic and germ stem cells leading to long-term genotoxic effects and azoospermia, while ABVD chemotherapy affects transiently sperm cells, with most of the patients showing recovery of spermatogenesis. Both regimens have long-term effects in somatic cells, presenting nonclonal chromosomal aberrations and genomic chaos in a fraction of noncancerous cells. This is a source of karyotypic heterogeneity that could eventually generate a more stable population acquiring clonal chromosomal aberrations and leading towards the development of a new cancer.
Topics: Antineoplastic Agents; Chromosome Aberrations; DNA Damage; Genomic Instability; Germ Cells; Hodgkin Disease; Humans
PubMed: 30634664
DOI: 10.3390/genes10010037 -
Cancer Genomics & Proteomics 2022Chromosomal translocations in cancer as well as benign neoplasias typically lead to the formation of fusion genes. Such genes may encode chimeric proteins when two... (Review)
Review
Chromosomal translocations in cancer as well as benign neoplasias typically lead to the formation of fusion genes. Such genes may encode chimeric proteins when two protein-coding regions fuse in-frame, or they may result in deregulation of genes via promoter swapping or translocation of the gene into the vicinity of a highly active regulatory element. A less studied consequence of chromosomal translocations is the fusion of two breakpoint genes resulting in an out-of-frame chimera. The breaks then occur in one or both protein-coding regions forming a stop codon in the chimeric transcript shortly after the fusion point. Though the latter genetic events and mechanisms at first awoke little research interest, careful investigations have established them as neither rare nor inconsequential. In the present work, we review and discuss the truncation of genes in neoplastic cells resulting from chromosomal rearrangements, especially from seemingly balanced translocations.
Topics: Humans; Translocation, Genetic; Neoplasms; Chromosome Aberrations; Gene Fusion; Promoter Regions, Genetic
PubMed: 36316036
DOI: 10.21873/cgp.20349 -
Cytogenetic and Genome Research 2006Chromosome bar codes are multicolor banding patterns produced by fluorescence in situ hybridization (FISH) with differentially labeled and pooled sub-regional DNA... (Review)
Review
Chromosome bar codes are multicolor banding patterns produced by fluorescence in situ hybridization (FISH) with differentially labeled and pooled sub-regional DNA probes. These molecular cytogenetic tools facilitate chromosome identification and the delineation of both inter- and intra-chromosomal rearrangements. We present an overview of the various conceptual approaches which can be largely divided into two classes: Simple bar codes designed for chromosome identification and complex bar codes for high resolution aberration screening of entire karyotypes. We address the issue of color redundancy and how to overcome this limitation by complementation of bar codes with whole chromosome painting probes.
Topics: Chromosome Aberrations; Chromosome Banding; Chromosome Mapping; Chromosome Painting; DNA Probes; Electronic Data Processing; Gene Rearrangement; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Translocation, Genetic
PubMed: 16954661
DOI: 10.1159/000094208 -
International Journal of Molecular... Aug 2022Ionizing radiation causes chromosome aberrations, which are possible biomarkers to assess space radiation cancer risks. Using the Monte Carlo codes Relativistic Ion...
Ionizing radiation causes chromosome aberrations, which are possible biomarkers to assess space radiation cancer risks. Using the Monte Carlo codes Relativistic Ion Tracks (RITRACKS) and Radiation-Induced Tracks, Chromosome Aberrations, Repair and Damage (RITCARD), we investigated how geometrical properties of the cell nucleus, irradiated with ion beams of linear energy transfer (LET) ranging from 0.22 keV/μm to 195 keV/μm, influence the yield of simple and complex exchanges. We focused on the effect of (1) nuclear volume by considering spherical nuclei of varying radii; (2) nuclear shape by considering ellipsoidal nuclei of varying thicknesses; (3) beam orientation; and (4) chromosome intermingling by constraining or not constraining chromosomes in non-overlapping domains. In general, small nuclear volumes yield a higher number of complex exchanges, as compared to larger nuclear volumes, and a higher number of simple exchanges for LET < 40 keV/μm. Nuclear flattening reduces complex exchanges for high-LET beams when irradiated along the flattened axis. The beam orientation also affects yields for ellipsoidal nuclei. Reducing chromosome intermingling decreases both simple and complex exchanges. Our results suggest that the beam orientation, the geometry of the cell nucleus, and the organization of the chromosomes within are important parameters for the formation of aberrations that must be considered to model and translate in vitro results to in vivo risks.
Topics: Cell Nucleus; Chromosome Aberrations; Chromosomes; Humans; Linear Energy Transfer; Monte Carlo Method
PubMed: 35955776
DOI: 10.3390/ijms23158638 -
International Journal of Molecular... Nov 2021The long-standing question in radiation and cancer biology is how principles of chromosome organization impact the formation of chromosomal aberrations (CAs). To address...
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.
Topics: Animals; Chromosome Aberrations; Chromosomes; DNA Breaks, Double-Stranded; Deoxyribonucleases; G1 Phase; Genetic Heterogeneity; High-Throughput Nucleotide Sequencing; Mice; Models, Theoretical; Molecular Conformation; Physical Phenomena; Precursor Cells, B-Lymphoid; Radiation, Ionizing; Translocation, Genetic
PubMed: 34830065
DOI: 10.3390/ijms222212186 -
Journal of Radiation Research Dec 1991The respective average annual doses are about 330 and 110 mR/yr, in the high background radiation areas (HBRA) in Yangjiang County and the control areas (CA) in Enping... (Review)
Review
The respective average annual doses are about 330 and 110 mR/yr, in the high background radiation areas (HBRA) in Yangjiang County and the control areas (CA) in Enping and Taishan Counties. Both the HBRA and CA are in Guangdong Province which borders the South China Sea. The frequencies of chromosome aberration in circulating lymphocytes were examined for persons residing in the HBRA and CA. Those in the HBRA had increased frequencies of detectable abnormalities in stable aberrations (translocations and inversions) and unstable aberrations (dicentrics and rings). Previous reports have shown that when samples of circulating lymphocytes taken from inhabitants were tested in vitro for mitotic responses to phytohemagglutinin (PHA) and for the degree of unscheduled DNA synthesis (UDS) induced by UV-irradiation, there were higher responsiveness and UDS rates for those in the HBRA than in the CA. In contrast, mortality from all cancers and those from leukemia, breast and lung cancers that are inducible by radiation was not higher in the HBRA. Although the differences in the cancer mortality rates for the HBRA and CA are not significant, the findings are compatible with the assumption that the lower mortality from cancer in the HBRA is the result of the hormetic effects of the three-fold higher dose rate of background radiation in that areas. This assumption requires further study.
Topics: Adolescent; Adult; Background Radiation; China; Chromosome Aberrations; Female; Humans; Male; Middle Aged; Neoplasms; Radiation Dosage; Radiation Effects
PubMed: 1823366
DOI: No ID Found -
Ecotoxicology and Environmental Safety Jul 2023There has been some controversy over the use of radiobiological models when modeling the dose-response curves of ionizing radiation (IR)-induced chromosome aberration...
There has been some controversy over the use of radiobiological models when modeling the dose-response curves of ionizing radiation (IR)-induced chromosome aberration and tumor prevalence, as those curves usually show obvious non-targeted effects (NTEs) at low doses of high linear energy transfer (LET) radiation. The lack of understanding the contribution of NTEs to IR-induced carcinogenesis can lead to distinct deviations of relative biological effectiveness (RBE) estimations of carcinogenic potential, which are widely used in radiation risk assessment and radiation protection. In this work, based on the initial pattern of two classes of IR-induced DNA double-strand breaks (DSBs) clustering in chromatin domains and the subsequent incorrect repair processes, we proposed a novel radiobiological model to describe the dose-response curves of two carcinogenic-related endpoints within the same theoretical framework. The representative experimental data was used to verify the consistency and validity of the present model. The fitting results indicated that, compared with targeted effect (TE) and NTE models, the current model has better fitting ability when dealing with the experimental data of chromosome aberration and tumor prevalence induced by multiple types of IR with different LETs. Notably, the present model without introducing an NTE term was adequate to describe the dose-response curves of IR-induced chromosome aberration and tumor prevalence with NTEs in low-dose regions. Based on the fitting parameters, the LET-dependent RBE values were calculated for three given low doses. Our results showed that the RBE values predicted by the current model gradually decrease with the increase of doses for the endpoints of chromosome aberration and tumor prevalence. In addition, the calculated RBE was also compared with those evaluated from other models. These analyses show that the proposed model can be used as an alternative tool to well describe dose-response curves of multiple carcinogenic-related endpoints and effectively estimate RBE in low-dose regions.
Topics: Humans; DNA Breaks, Double-Stranded; Chromatin; Prevalence; Linear Energy Transfer; Radiation, Ionizing; Chromosome Aberrations; Neoplasms; DNA; Cluster Analysis; Dose-Response Relationship, Radiation
PubMed: 37229870
DOI: 10.1016/j.ecoenv.2023.115038