The Breakage-Fusion-Bridge Cycle Producing MLL Amplification in a Case of Myelodysplastic Syndrome

Telomere loss may lead to chromosomal instability via the breakage-fusion-bridge (BFB) cycle which can result in genetic amplification and the formation of ring and dicentric chromosomes. This cycle continues until stable chromosomes are formed. The case of a 72-year-old female with refractory anaemia with excess blasts type 2 illustrates these events. Conventional cytogenetics produced a complex karyotype which included unstable abnormalities of chromosomes 11, 12, and 15. Fluorescence in situ hybridization (FISH) analyses including multicolor-FISH (M-FISH) and multicolor-banding (M-BAND) revealed multiple clonal populations with 5 copies of MLL on either a ring chromosome composed entirely of chromosome 11 material or a derivative chromosome composed of chromosomes 11, 12, and 15. The FISH results also clarified the likely evolution of the karyotypic complexity. The simplest cell line contained a dic(12;15) in addition to copy number aberrations that are typical of MDS or AML. As the disease progressed, a ring 11 was formed. Subsequently, the ring 11 appears to have unwound and inserted itself into the dic(12;15) chromosome followed by an inversion of the derivative chromosome, producing a der(11;15;12). Telomeric loss and BFB cycles appear to have played an important role in the chromosomal rearrangements and clonal evolution demonstrated in the karyotype.

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Routes of Clonal Evolution into Complex Karyotypes in Myelodysplastic Syndrome Patients with 5q Deletion

International Journal of Molecular Sciences ◽

10.3390/ijms19103269 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3269 ◽

Cited By ~ 1

Author(s):

Simone Feurstein ◽

Kathrin Thomay ◽

Winfried Hofmann ◽

Guntram Buesche ◽

Hans Kreipe ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Clonal Evolution ◽

Suppressor Gene ◽

Trisomy 8 ◽

Multicolor Fish ◽

Catastrophic Event ◽

Evolution And Development ◽

Gene Tp53

Myelodysplastic syndrome (MDS) can easily transform into acute myeloid leukemia (AML), a process which is often associated with clonal evolution and development of complex karyotypes. Deletion of 5q (del(5q)) is the most frequent aberration in complex karyotypes. This prompted us to analyze clonal evolution in MDS patients with del(5q). There were 1684 patients with low and intermediate-risk MDS and del(5q) with or without one additional cytogenetic abnormality, who were investigated cytogenetically in our department, involving standard karyotyping, fluorescence in situ hybridization (FISH) and multicolor FISH. We identified 134 patients (8%) with aspects of clonal evolution. There are two main routes of cytogenetic clonal evolution: a stepwise accumulation of cytogenetic events over time and a catastrophic event, which we defined as the occurrence of two or more aberrations present at the same time, leading to a sudden development of highly complex clones. Of the 134 patients, 61% underwent a stepwise accumulation of events whereas 39% displayed a catastrophic event. Patients with isolated del(5q) showed significantly more often a stepwise accumulation of events rather than a catastrophic event. The most frequent aberrations in the group of stepwise accumulation were trisomy 8 and trisomy 21 which were significantly more frequent in this group compared to the catastrophic event group. In the group with catastrophic events, del(7q)/-7 and del(17p)/-17 were the most common aberrations. A loss of 17p, containing the tumor suppressor gene TP53, was found significantly more frequent in this group compared to the group of stepwise accumulation. This leads to the assumption that the loss of TP53 is the driving force in patients with del(5q) who undergo a sudden catastrophic event and evolve into complex karyotypes.

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ANALYSIS OF COMPLEX CHROMOSOMAL ABNORMALITIES IN A CASE OF MULTIPLE MYELOMA USING SPECTRAL KARYOTYPING

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i9.27133 ◽

2018 ◽

Vol 11 (9) ◽

pp. 9

Author(s):

Perumal Govindasamy ◽

Pooja S Kulshreshtha ◽

Prabu Pandurangan ◽

Anil Tarigopula ◽

Jayarama S Kadandale ◽

...

Keyword(s):

Multiple Myeloma ◽

Chromosomal Abnormalities ◽

Bone Marrow Cells ◽

Spectral Karyotyping ◽

Multicolor Fish ◽

Genetic Abnormalities ◽

Prognostic Outcome ◽

Conventional Cytogenetics ◽

Marrow Cells

Objective: It was proposed to determine the chromosomal abnormalities in a 49-year-old male patient with multiple myeloma (MM) employing both conventional and advanced molecular cytogenetic techniques.Methods: GTG-banding and spectral karyotyping (SKY) on fixed metaphases obtained from LPS-stimulated bone marrow cells and interphase fluorescence in situ hybridization (iFISH) on unsorted marrow cells were carried out to identify genetic markers of prognostic significance.Results: The abnormal chromosomes observed through conventional cytogenetics could be resolved with SKY technique. The translocation t(4;14) (p16;q32) indicating FGFR3/IGH fusion and deletion of 13q14.3 was noticed using iFISH. The genetic abnormalities confirmed a poor prognostic outcome in the patient who died within 6 months of diagnosis.Conclusion: This report emphasizes the need for multicolor FISH techniques besides iFISH to resolve complex abnormalities and to identify cryptic aberrations of importance in risk stratification of MM patients.

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Human Ring Chromosomes – New Insights for their Clinical Significance

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2013-0013 ◽

2013 ◽

Vol 16 (1) ◽

pp. 13-19 ◽

Cited By ~ 4

Author(s):

R.S. Guilherme ◽

E Klein ◽

A.B. Hamid ◽

S Bhatt ◽

M Volleth ◽

...

Keyword(s):

In Situ Hybridization ◽

Clinical Signs ◽

Ring Chromosome ◽

Signs And Symptoms ◽

Molecular Techniques ◽

Ring Chromosomes ◽

Multicolor Banding ◽

Clinical Signs And Symptoms ◽

Clinical Problems

Abstract Twenty-nine as yet unreported ring chromosomes were characterized in detail by cytogenetic and molecular techniques. For FISH (fluorescence in situ hybridization) previously published high resolution approaches such as multicolor banding (MCB), subcentromere-specific multi-color-FISH (cenM-FISH) and two to three-color-FISH applying locus-specific probes were used. Overall, ring chromosome derived from chromosomes 4 (one case), 10 (one case), 13 (five cases), 14, (three cases), 18 (two cases), 21 (eight cases), 22 (three cases), X (five cases) and Y (one case) were studied. Eight cases were detected prenatally, eight due developmental delay and dysmorphic signs, and nine in connection with infertility and/or Turner syndrome. In general, this report together with data from the literature, supports the idea that ring chromosome patients fall into two groups: group one with (severe) clinical signs and symptoms due to the ring chromosome and group two with no obvious clinical problems apart from infertility.

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Pseudodicentric Chromosome Originating from Autosomes 9 and 21 in a Male Patient with Oligozoospermia

Cytogenetic and Genome Research ◽

10.1159/000504820 ◽

2019 ◽

Vol 159 (4) ◽

pp. 201-207

Author(s):

Marion Beaumont ◽

Elena J. Tucker ◽

Laura Mary ◽

Erika Launay ◽

Yann Lurton ◽

...

Keyword(s):

Male Infertility ◽

Genetic Factors ◽

Chromosomal Rearrangements ◽

Chromosomal Anomalies ◽

Derivative Chromosome ◽

Telomeric Sequences ◽

Dicentric Chromosomes ◽

Interstitial Telomeric Sequences ◽

Cytogenetic Analyses ◽

Reproductive Phenotype

Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies (related to the Y chromosome or to the autosomes) are validated genetic factors leading to spermatogenic quantitative defects with a frequency depending on the severity of the phenotype. The most frequent structural chromosomal rearrangements of autosomes are translocations and inversions, whereas dicentric chromosomes involving autosomes are rare. We report a man bearing a pseudodicentric chromosome (9;21) and presenting with oligozoospermia. Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome and to discount the presence of interstitial telomeric sequences. Defects in spermatogenesis and abnormal segregation at meiosis for existing spermatozoa are proposed and are the likely cause of the reproductive phenotype of the patient.

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Frequent Clonal Evolution in Multiple Myeloma,

Blood ◽

10.1182/blood.v118.21.3919.3919 ◽

2011 ◽

Vol 118 (21) ◽

pp. 3919-3919

Author(s):

Sang Mee Hwang ◽

Jungeun Choi ◽

Sunhee Yim ◽

Tae Young Kim ◽

Chaja See ◽

...

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Prognostic Factors ◽

In Situ Hybridization ◽

Clonal Evolution ◽

Chromosome 1 ◽

Structural Abnormalities ◽

Conventional Cytogenetics

Abstract Abstract 3919 Background: Multiple myeloma is a clonal bone marrow disease characterized by the neoplastic transformation of differentiated B cells. Various complex cytogenetic and molecular genetic aberrations are present that are important for prognostication and follow up investigation. We investigated the clonal evolution of multiple myeloma patients at relapse or at progression compared from the diagnosis by conventional cytogenetics, fluorescence in situ hybridization (FISH) and cytoplasmic immunoglobulin fluroscence in situ hybridization (cIg FISH). Methods: 35 patients diagnosed as multiple myeloma by bone marrow examination from January 2003 to March 2011 were included. Conventional cytogenetics were performed in all patients at diagnosis and at relapse or progression. FISH was performed in 24 patients with available specimen for at least 3 items including −13/del(13q), p53 deletion/del(17p), 1q21 gain, p16 deletion, IgH rearrangement, t(4;14) and t(14;16). The FISH results were confirmed with cytoplasmic immunoglobulin FISH specifically staining plasma cells. Results: Forty-nine percent of the patients had relapsed or progressed with additional clonal evolutions and they were detected by conventional cytogenetics. Numerical abnormalities were more frequent than structural abnormalities and structural abnormalities involving chromosome 1 was frequent. Thirty-five percent had developed −13/13q loss which is considered a poor prognostic factor. cIg-FISH found additional aberrations in 20% of the patients such as RB1 deletion, del(17p) and t(14;16). Conclusion: Conventional cytogenetics and cIG-FISH are both necessary in relapsed patient since clonal evolutions develop in many patients which may only be detected by one method. Full evaluation of cIg-FISH including non-poor prognostic factors may be considered since new clones evolve that can be a candidate of follow-up marker and since prognostic factors can change as treatment modality changes. Disclosures: No relevant conflicts of interest to declare.

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Unusual de novo Partial Trisomy 17p12p11.2 due to Unbalanced Insertion into 5p13.1 in a Severely Affected Boy

Journal of Pediatric Genetics ◽

10.1055/s-0037-1599195 ◽

2017 ◽

Vol 06 (03) ◽

pp. 165-168 ◽

Cited By ~ 2

Author(s):

Luis Mendez-Rosado ◽

Araceli Lantigua ◽

Juan Galarza ◽

Ahmed Hamid Al-Rikabi ◽

Monika Ziegler ◽

...

Keyword(s):

De Novo ◽

Chromosomal Rearrangements ◽

Partial Trisomy ◽

Derivative Chromosome ◽

Genomic Disorder ◽

Charcot Marie Tooth Disease ◽

Dysmorphic Features ◽

Copy Numbers ◽

Tooth Disease

AbstractGain of copy numbers can be due to different chromosomal rearrangements such as direct or indirect duplications, translocations, small supernumerary marker chromosomes, or insertions. In a 3-year-old boy with dysmorphic features and developmental delay, chromosome analyses revealed a derivative chromosome 5. Microdissection and reverse fluorescence in situ hybridization identified the in 5p13.1 inserted part as 17p12-p11.2 material. Thus the patient suffered from a rare combination of genomic disorder, that is, Charcot-Marie-Tooth disease type 1A and Potocki-Lupski syndrome. Parental studies indicated that the abnormality was de novo in origin. As the question how this rearrangement arose cannot be answered conclusively, formal genetic counseling is warranted, which includes a discussion regarding the possibility of gonadal mosaicism. In conclusion, this case highlights that chromosome 17p is genetically relatively instable, and thus it can lead to rare chromosomal conditions.

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Chromosomal rearrangements in Arabidopsis mutants revealed by repeated FISH

Plant Soil and Environment ◽

10.17221/2206-pse ◽

2008 ◽

Vol 53 (No. 7) ◽

pp. 325-328

Author(s):

P. Mokroš

Keyword(s):

Dna Damage ◽

Genetic Information ◽

Chromosomal Rearrangements ◽

Nuclear Genome ◽

Necessary Condition ◽

Anaphase Bridges ◽

Cell Lineages ◽

Dicentric Chromosomes ◽

The Stability

The stability of plant nuclear genome is a necessary condition for the faithful transmission of genetic information through cell lineages. When DNA damage occurs due to various impairments, cells start a number of repair processes including ligation of broken chromosomes. As a result, dicentric chromosomes can be formed. Dicentrics are easily detectable as anaphase bridges during following mitosis. Using Arabidopsis as a model plant, we developed a sensitive cytogenetic assay to identify specific chromosomal rearrangements. Here we show Arabidopsis tert−/− and atm−/− mutants and their chromosome rearrangements and fusions analysed by fluorescence in situ hybridization (FISH). The method is based on successive rounds of FISH with chromosome-specific probes and the comparison of resulting FISH images.

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Clonal evolution in chronic lymphocytic leukemia detected by fluorescence in situ hybridization and conventional cytogenetics after stimulation with CpG oligonucleotides and interleukin-2: A prospective analysis

Leukemia Research ◽

10.1016/j.leukres.2013.10.019 ◽

2014 ◽

Vol 38 (2) ◽

pp. 170-175 ◽

Cited By ~ 10

Author(s):

Martin Brejcha ◽

Martina Stoklasová ◽

Yvona Brychtová ◽

Anna Panovská ◽

Kristina Štěpanovská ◽

...

Keyword(s):

In Situ Hybridization ◽

Chronic Lymphocytic Leukemia ◽

Fluorescence In Situ Hybridization ◽

Clonal Evolution ◽

Interleukin 2 ◽

Lymphocytic Leukemia ◽

Prospective Analysis ◽

Cpg Oligonucleotides ◽

Conventional Cytogenetics

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Two Separate Cases: Complex Chromosomal Abnormality Involving Three Chromosomes and Small Supernumerary Marker Chromosome in Patients with Impaired Reproductive Function

Genes ◽

10.3390/genes11121511 ◽

2020 ◽

Vol 11 (12) ◽

pp. 1511

Author(s):

Tatyana V. Karamysheva ◽

Tatyana A. Gayner ◽

Vladimir V. Muzyka ◽

Konstantin E. Orishchenko ◽

Nikolay B. Rubtsov

Keyword(s):

Genetic Counseling ◽

Chromosome Rearrangement ◽

Marker Chromosome ◽

Reproductive Function ◽

Small Supernumerary Marker Chromosome ◽

Comprehensive Chromosome Screening ◽

The Family ◽

Multicolor Banding ◽

The One

For medical genetic counseling, estimating the chance of a child being born with chromosome abnormality is crucially important. Cytogenetic diagnostics of parents with a balanced karyotype are a special case. Such chromosome rearrangements cannot be detected with comprehensive chromosome screening. In the current paper, we consider chromosome diagnostics in two cases of chromosome rearrangement in patients with balanced karyotype and provide the results of a detailed analysis of complex chromosomal rearrangement (CCR) involving three chromosomes and a small supernumerary marker chromosome (sSMC) in a patient with impaired reproductive function. The application of fluorescent in situ hybridization, microdissection, and multicolor banding allows for describing analyzed karyotypes in detail. In the case of a CCR, such as the one described here, the probability of gamete formation with a karyotype, showing a balance of chromosome regions, is extremely low. Recommendation for the family in genetic counseling should take into account the obtained result. In the case of an sSMC, it is critically important to identify the original chromosome from which the sSMC has been derived, even if the euchromatin material is absent. Finally, we present our view on the optimal strategy of identifying and describing sSMCs, namely the production of a microdissectional DNA probe from the sSMC combined with a consequent reverse painting.

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