Jumping translocations are common in solid tumor cell lines and result in recurrent fusions of whole chromosome arms

Jumping translocations (JTs) and segmental jumping translocations (SJTs) are unbalanced translocations involving a donor chromosome arm or chromosome segment that has fused to multiple recipient chromosomes. In leukemia, where JTs have been predominantly observed, the donor segment (usually 1q) preferentially fuses to the telomere regions of recipient chromosomes. In this study, spectral karyotyping (SKY) and FISH analysis revealed 188 JTs and SJTs in 10 cell lines derived from carcinomas of the bladder, prostate, breast, cervix, and pancreas. Multiple JTs and SJTs were detected in each cell line and contributed to recurrent unbalanced whole-arm translocations involving chromosome arms 5p, 14q, 15q, 20q, and 21q. Sixty percent (113/188) of JT breakpoints occurred within centromere or pericentromeric regions of the recipient chromosomes, whereas only 12% of the breakpoints were located in the telomere regions. JT breakpoints of both donor and recipient chromosomes coincided with numerous fragile sites as well as viral integration sites for human DNA viruses. The JTs within each tumor cell line promoted clonal progression, leading to the acquisition of extra copies of the donated chromosome segments that often contained oncogenes (MYC, ABL, HER2/NEU, etc.), consequently resulting in tumor-specific genomic imbalances. Published 2001 Wiley-Liss, Inc.     

Jumping translocations

Jumping translocations (JT) are uncommon constitutional or acquired chromosome rearrangements involving one donor and several recipient chromosomes. They occur in various pathologic conditions and the mechanism of their formation remains elusive. A review of the literature showed that the major localizations of the breakpoints of JTs in human samples are nonrandomly located in pericentromeric and telomeric regions of chromosomes. Interestingly, comparison of the localization of the chromosomal breakpoints and of presence of interstitial DNA repeats showed differences between constitutional and acquired JTs suggesting differences in the mechanisms for the genesis of JTs and their consequences.     

Types, stability, and phenotypic consequences of chromosome rearrangements leading to interstitial telomeric sequences.

Using in situ hybridisation, we identified interstitial telomeric sequences in seven chromosomal translocations present in normal and in syndromic subjects. Telomeric sequences were also found at the centromeric ends of a 4p and a 4q caused by centric fission of one chromosome 4. We found that rearrangements leading to interstitial telomeric sequences were of three types: (1) termino-terminal rearrangements with fusion of the telomeres of two chromosomes, of which we report one case; (2) rearrangements in which an acentric fragment of one chromosome fuses to the telomere of another chromosome. We describe four cases of Prader-Willi syndrome with the 15q1-qter transposed to the telomeric repeats of different recipient chromosomes; (3) telomere-centromere rearrangements in which telomeric sequences of one chromosome fuse with the centromere of another chromosome. We describe two examples of these rearrangements in which not only telomeric sequences but also remnants of alphoid sequences were found at the fusion point. Instability at the fusion point of the derivative chromosome was found in the Prader-Willi translocations but we were unable to correlate this instability with culture conditions. The two subjects with the termino-terminal rearrangement and the centric fission respectively have normal phenotypes. The two patients with telomere-centromere fusions were unbalanced for the short arm of an acrocentric chromosome and had failure to thrive; one of them also had dysmorphic facies. We postulate that these phenotypes could be the result of uniparental disomy.     

Jumping translocations of 11q in acute myeloid leukemia and 1q in follicular lymphoma

Jumping translocation is a rare cytogenetic aberration in leukemia and lymphoma, and its etiologic mechanisms are not clearly known. We report two cases with jumping translocations. One had follicular lymphoma and jumping translocations of 1q onto the telomeric regions of 5p, 9p, and 15q in three cell lines, co-existing with the specific translocation t(14;18)(q32;q21). The second case had acute myeloid leukemia (AML) and jumping translocations of 11q as the sole aberration, onto multiple derivative chromosomes in each of the abnormal cells. A total of 17 telomeric regions were seen as the recipients of 11q in this case, and 9q was always involved as one of the recipients in all abnormal cells. Fluorescence in situ hybridization (FISH) confirmed the identification of 11q material in the derivative chromosomes. While 1q has been the most common donor of acquired jumping translocations, this is the first report on jumping translocations of 11q. Different from all previously reported jumping translocations which involve only one recipient in each cell line and lead to a mosaic trisomy, multiple recipients in most of the abnormal cells in this case had led to a tetrasomy, or a pentasomy of 11q. The pattern of chromosome involvement as the recipients of 11q appears to show a continuing evolutionary process of jumping, stabilization, and spreading of the donor material into other chromosomes. Somatic recombinations between the interstitial telomeric or subtelomeric sequences of a derivative chromosome and the telomeric sequences of normal chromosomes are believed to be the underlying mechanism of jumping translocations and their clonal evolution.     

A constitutional telomeric translocation showing meiotic instability

Constitutional telomeric translocations are rare chromosome rearrangements. They are thought to occur as a result of chromosome breakage and subsequent ligation with the telomeric sequence of a different chromosome. Most frequently they occur as de novo events and, depending on the donor chromosome breakpoint, may be associated with an abnormal phenotype. We report a case of an unbalanced translocation involving the long arm of chromosome 15 and the short arm of chromosome 8 [45,XY, der(8)t(8;15)(p23.3;q11.2),-15], diagnosed prenatally; the father carried an unbalanced translocation of the long arm of chromosome 15 and the short arm of chromosome 2 [45,XY,der(2)t(2;15)(p25.3;q11.2),-15]. Both translocations were shown to have telomere repeat sequences at the translocation breakpoints. There was no apparent imbalance of euchromatic material in either translocation, and no associated abnormal phenotype.     

PRINS Analysis of the Telomeric Sequence in Seven Lemurs

We examined the chromosomal localization of the telomeric sequence, (TTAGGG)_n, in seven species of the lemurs and one greater galago, as an outgroup, using the primed in-situ labeling (PRINS) technique. As expected, the telomeric sequence was identified at both ends of all chromosomes of the eight prosimians. However, six species showed a signal at some pericentromeric regions involving constitutive heterochromatin as well. The pericentromeric region of chromosome 1 of Verreaux's sifaka (Propithecus verreauxi verreauxi) was labeled with a large and intense signal. The range of the signal considerably exceeded the area of DAPI positive heterochromatin. On the other hand, in the five lemurs, a large signal was detected also in the short arm of acrocentric chromosomes. Acquisition of the large block of the telomeric sequence into the acrocentric short arm might be interpretable in terms of the tandem growth of the heterochromatic short arm and the reciprocal translocation between heterochromatic short arms involving the telomeric sequence. Subsequently, it was postulated that meta- or submetacentric chromosomes possessing the telomeric sequence at the pericentromeric region could be formed by centric fusion between such acrocentric chromosomes.     

Jumping translocations: Short telomeres or pathogenic TP53 variants as underlying mechanism in acute myeloid leukemia and myelodysplastic syndrome?

Chromosomal rearrangements involving one donor chromosome and two or more recipient chromosomes are called jumping translocations. To date only few cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with jumping translocations have been described and the underlying mechanisms remain unclear. Here, we analyzed 11 AML and 5 MDS cases with jumping translocations. The cases were analyzed by karyotyping, FISH, telomere length measurement, and next‐generation sequencing with an AML/MDS gene panel. Cases with jumping translocations showed significantly (P < .01) shorter telomeres in comparison to healthy age‐matched controls. Additional neo‐telomeres were found in two cases. In total, eight cases showed recipient chromosomes with a breakpoint in the centromeric region all of them harboring a pathogenic variant in the TP53 gene (n = 6) and/or a loss of TP53 (n = 5). By contrast, no pathogenic variant or loss of TP53 was identified in the six cases showing recipient chromosomes with a breakpoint in the telomeric region. In conclusion, our results divide the cohort of AML and MDS cases with jumping translocations into two groups: the first group with a telomeric breakpoint of the recipient chromosome is characterized by short telomeres and a possibly telomere‐based mechanism of chromosomal instability formation. The second group with a centromeric breakpoint of the recipient chromosome is defined by mutation and/or loss of TP53. We, therefore, assume that both critically short telomeres as well as pathogenic variants of TP53 influence jumping translocation formation.     

The conundrum of a jumping translocation (JT) in CVS from twins and review of JTs

Jumping translocations (JTs) are rare constitutional or acquired rearrangements involving a donor and several receiver chromosomes. They may be inherited or de novo. JTs can be found as a cultural artifact, in normal individuals or in pathological conditions. The clinical consequences range from spontaneous abortion, loss of fetus, chromosome syndrome, congenital abnormalities, and infertility to malignancy. Considering the breakpoints of JTs, they are localized predominantly in repeat regions such as pericentromeric, centromeric, subtelomeric, telomeric, and occasionally interstitial regions that may be in a low copy repeats (LCR) or in a telomere like sequence. Differences between the constitutional and acquired JTs donor breakpoints suggest an independent mechanism in their formation. In this review, a new JT involving a donor chromosome 18p10qter and recipients 17q25qter or 1q25qter found by CVS of a twin pregnancy is described. This case illustrates the diagnostic challenges posed by JTs.In this study, our knowledge on JTs is consolidated to improve identification, management, and counseling.     

Jumping translocation in a phenotypically normal female

"Jumping translocation" (jt) refers to a rare type of chromosome mosaic, in which the same portion of a (donor) chomosome is translocated to different (recipient) chromosome sites. It have mainly been observed in lymphocyte cultures of patients with hematologic malignancies. We report a phenotypically normal female carrying a mosaic of two cell lines with the Xq26-qter segment translocated to the short arm of chromosomes 15 or 21 in peripheral blood lymphocytes. In skin fibroblasts, only the X/21 translocation was detected. We speculate that recombination between homologous repetitive sequences on non-homologous human acrocentrics may be the cause of such chromosomal rearrangements.     

Jumping translocation of 1q in a BCR/ABL-positive acute lymphoblastic leukemia

Jumping translocations (JT) are rare chromosomal abnormalities in which an identical copy of a chromosomal region (donor) is translocated to a different chromosome (acceptor). Chromosome 1 is often involved as donor chromosome. JTs of the long arm of chromosome 1 (1q) or parts of it are associated with a poor outcome. We report on a 72-year-old male patient with a BCR/ABL1 rearrangement positive acute lymphoblastic leukemia (common ALL, or c-ALL; FAB L2 morphology) and with additional structural and numeric aberrations. Four aberrant clones were observed after conventional cytogenetic analysis. Three of the four clones showed a JT with 1q as donor and 3q, 8q, and 22q as acceptors. To the best of our knowledge, neither JT between 1q and chromosome 3 nor JT between 1q and chromosome 22 have been described in c-ALL. This report emphasizes the frequent involvement of 1q in JT and the association with a poor prognosis.     

A unique, complex variant philadelphia chromosome translocation in a patient with typical chronic myelogenous leukemia

The Philadelphia (Ph) chromosome [der(22) t(9;22)(q34;q11)] is the characteristic chromosomal abnormality found in chronic myelogenous leukemia (CML). This chromosome has been reported in patients with other chromosomal abnormalities. In this study, we describe a patient with hematologically typical chronic-phase CML with an unusual and complex translocation involving chromosomes 9, 11, and 22. These complex translocations were identified by G-banded conventional cytogenetics and confirmed by fluorescence in situ hybridization (FISH) using whole chromosome painting probes (wcp). To the best of our knowledge, these are unique translocations involving the short and the long arms of chromosome 9 in 4 different translocations with the short arm of chromosome 11 and the long arm of chromosome 22.     

Combined 24-color karyotyping and comparative genomic hybridization analysis indicates predominant rearrangements of early replicating chromosome regions in neuroblastoma

Neuroblastoma is characterized by several distinct genetic alterations including MYCN amplification, chromosome 1p deletion and gain of chromosome 17. Although these alterations are thought to play a crucial role in oncogenesis, to date little is known about their underlying mechanisms. In order to more precisely document these genetic alterations, we have performed a combined study of 27 neuroblastoma cell lines using 24-color karyotyping (24-CK) and comparative genomic hybridization (CGH). 24-CK detected balanced translocations in 13 cases with recurrent involvement of chromosome 8. More importantly, 144 nonreciprocal translocations were observed in the 27 cell lines, with chromosome 1 as the most frequent recipient and chromosome 17 the most frequent donor. Each cell line exhibited at least one unbalanced translocation involving 17q, with 14 cell lines demonstrating more than one such translocation. Other recurrent alterations were amplification of the 2p24 chromosome region, which encodes the MYCN oncogene, losses of 1p, 3p and 11q, and gains of 1q and 7. In most cases, CGH profiles were directly linked to the presence of unbalanced translocations with gain of the donor fragment and loss of the replaced region on the recipient chromosome. Strikingly, over 60% of the chromosome breakpoints mapped to early replicating chromosome bands, which represent around 13% of the genome. Altogether these data suggest that neuroblastoma is characterized by rearrangements that predominantly involve chromosome fragments replicating early in the S-phase.     

Intrachromosomal distribution of telomeric repeats in Eumops glaucinus and Eumops perotis (Molossidae, Chiroptera)

The location of chromosomal telomeric repeats (TTAGGG)_n was investigated in two species of the Molossidae family, Eumops glaucinus and Eumops perotis. The diploid chromosome number (2n) is 40 in E. glaucinus and 48 in E. perotis and the fundamental numbers (FN) are 64 and 58, respectively. It has been suggested that the E. glaucinus karyotype has evolved from the E. perotis karyotype through Robertsonian fusion events. In the present study, the telomeric sequences were detected at the termini of chromosomes in both species. In addition, E. glaucinus also displayed telomeric repeats in centromeric and pericentromeric regions in almost all biarmed chromosomes. Conversely, in E. perotis pericentromeric signals were only observed in two biarmed chromosomes. In both E. glaucinus and E. perotis, such telomeric sequences were observed as part of the heterochromatin. The interstitial sites of telomeric sequences suggest that they are remnants of telomeres of ancestral chromosomes that participated in the fusion event.     

Detection of genetic alterations in primary bladder carcinoma with dual-color and multiplex fluorescence in situ hybridization

Cytogenetic studies of bladder cancer have shown several nonrandom aberrations. Numerical aberrations of both sex chromosomes were investigated in 32 primary bladder tumors with bicolor fluorescence in situ hybridization (FISH). Loss of chromosome Y and overrepresentation of chromosome X were observed in subgroups of male patients. Chromosome X was represented normally in female patients. Two of the above primary bladder tumors, a transitional cell carcinoma (TCC) and an adenocarcinoma, were further analyzed with both multiplex FISH (24-color M-FISH) and G-banding. Both cases exhibited 1) common breakpoints on 5q11 approximately q12 and 15q24; 2) involvement of the pericentromeric area of chromosome 13; 3) structural abnormalities of chromosomes 8 and 17, with loss of material on the short arm; 4) structural abnormalities involving chromosome 11; and 5) loss of chromosome Y. The TCC case also exhibited structural abnormalities of chromosome 9, resulting in loss of 9q. The combined G-banding and M-FISH findings could help reveal regions potentially involved in bladder tumorigenesis.     

Selection against Robertsonian fusions involving housekeeping genes in the house mouse: integrating data from gene expression arrays and chromosome evolution

Monobrachial homology resulting from Robertsonian (Rb) fusions is thought to contribute to chromosomal speciation through underdominance. Given the karyotypic diversity characterizing wild house mouse populations [Mus musculus domesticus, (MMU)], variation that results almost exclusively from Rb fusions (diploid numbers range from 22 to 40) and possibly whole arm reciprocal translocations (WARTs), this organism represents an excellent model for testing hypotheses of chromosomal evolution. Previous studies of chromosome size and recombination rates have failed to explain the bias for certain chromosomes to be involved more frequently than others in these rearrangements. Here, we show that the pericentromeric region of one such chromosome, MMU19, which is infrequently encountered as a fusion partner in wild populations, is significantly enriched for housekeeping genes when compared to other chromosomes in the genome. These data suggest that there is selection against breakpoints in the pericentromeric region and provide new insights into factors that constrain chromosomal reorganizations in house mice. Given the anticipated increase in vertebrate whole genome sequences, the examination of gene content and expression profiles of the pericentromeric regions of other mammalian lineages characterized by Rb fusions (i.e., other rodents, bats, and bovids, among others) is both achievable and crucial to developing broadly applicable models of chromosome evolution.     

The Evolutionary Chromosome Translocation 4;19 in Gorilla gorilla is Associated with Microduplication of the Chromosome Fragment Syntenic to Sequences Surrounding the Human Proximal CMT1A-REP

Many genomic disorders occur as a result of chromosome rearrangements involving low-copy repeats (LCRs). To better understand the molecular basis of chromosome rearrangements, including translocations, we have investigated the mechanism of evolutionary rearrangements. In contrast to several intrachromosomal rearrangements, only two evolutionary translocations have been identified by cytogenetic analyses of humans and greater apes. Human chromosome 2 arose as a result of a telomeric fusion between acrocentric chromosomes, whereas chromosomes 4 and 19 in Gorilla gorilla are the products of a reciprocal translocation between ancestral chromosomes, syntenic to human chromosomes 5 and 17, respectively. Fluorescence in situ hybridization (FISH) was used to characterize the breakpoints of the latter translocation at the molecular level. We identified three BAC clones that span translocation breakpoints. One breakpoint occurred in the region syntenic to human chromosome 5q13.3, between the HMG-CoA reductase gene (HMGCR) and RAS p21 protein activator 1 gene (RASA1). The second breakpoint was in a region syntenic to human chromosome 17p12 containing the 24 kb region-specific low-copy repeat-proximal CMT1A-REP. Moreover, we found that the t(4;19) is associated with a submicroscopic chromosome duplication involving a 19p chromosome fragment homologous to the human chromosome region surrounding the proximal CMT1A-REP. These observations further indicate that higher order genomic architecture involving low-copy repeats resulting from genomic duplication plays a significant role in karyotypic evolution.     

PRINS tandem labeling of satellite DNA in the study of chromosome damage.

Tandem labeling of satellite DNA was proposed a few years ago (1) for evaluating preferential chromosome breaks in the pericentromeric regions of mammalian chromosomes, and (2) for distinguishing chromosome breaks from chromosome segregation errors in interphase cells. In the presence of primers and modified nucleotides, primed in situ labeling (PRINS) tags repetitive DNA sequences, and serves as a useful alternative to fluorescence in situ hybridization (FISH). We developed a two-color method for PRINS tandem labeling of centromeric and pericentromeric sequences. The method, which appears to be more sensitive than FISH, was used to assay micronuclei in mouse splenocytes and early spermatids, and it provided insight into mechanisms of induction of chromosome damage in these cells. We compared the sensitivity of this method and of a different two-color approach, based on simultaneous labeling of centromeric and telomeric sequences.     

Assisted reproductive technology and complex chromosomal rearrangements: the limits of ICSI

Complex chromosomal rearrangements are very rare events in the human population. According to our knowledge on the consequences of simple reciprocal translocations for male fertility, translocations involving three or more chromosomes are thought to lead to severe reproductive impairments in terms of meiotic disturbance or chromosomal imbalance of gametes. We report the case of a 48 year old man whose sperm count revealed either oligozoospermia (<10(3) spermatozoa/ml) or azoospermia. He was referred to the laboratory for in-vitro fertilization after intracytoplasmic sperm injection. Cytogenetic investigations showed a complex chromosomal rearrangement involving firstly a translocation between the short arm of chromosome 7 and the long arm of chromosome 13 and secondly a translocation between the short arm of the same chromosome 13 and the short arm of chromosome 9. Diagnosis was ascertained by fluorescence in-situ hybridization and staining of the nucleolar organizer regions. Theoretical study of the translocated chromosomes predicted a 'chain' configuration of the hexavalent at the pachytene stage of meiosis. In all, 32 modes of segregation were considered and only one resulted either in a normal or a balanced gamete karyotype. Genetic counselling and choice of appropriate artificial reproduction technique are discussed.      

Complex chromosome rearrangement involving chromosomes 1, 4 and 16 revealed by fluorescence in situ hybridization

A 7-year-old boy with mental retardation had apparently balanced reciprocal translocations, involving the telomeric regions of chromosomes 1p and 4q, which was detected by routine chromosome analysis. Fluorescence in situ hybridization (FISH) was used and also revealed the telomeric region of chromosome 16p to be involved in a still apparently balanced translocation-complex, impossible to discover with classical cytogenetic analysis. We want to emphasize the importance of FISH in detecting small chromosomal aberrations. We discuss whether the abnormal phenotype is caused by unbalanced karyotype with cryptic undetected translocations or small deletions or mutations in the translocation-breakpoints.     

Centromere-telomere (12;8p) fusion, telomeric 12q translocation, and i(12p) trisomy

The concurrence of a short arm isochromosome and a translocation of the entire long arm of the same chromosome to a telomere of another chromosome, implying trisomy for 4p, 5p, 7p, 9p, 10p or 12p, has been described in 13 patients. We have now used fluorescence in situ hybrization (FISH) to better characterize one of these rearrangements in which 12q was translocated to 8pter, whereas 12p was converted into an isochromosome. An alphoid centromere-12 repeat gave a strong signal on the i( 2p) and a weak but distinct signal at the breakpoint junction of the der(8), whereas the pantelomeric probe revealed three clear hybridization sites on the der(8): one at each end and another at the breakpoint junction. These findings suggest that the prime event was a post-fertilization centric fission of chromosome 12 leading to the 12q translocation via a real centromere telomere fusion and the i(12p). Alternatively, the crucial event may have been a centromere telomere recombination. An interstitial telomere has been documented by means of FISH at the breakpoint junction of the sole derivative usually present in 20 constitutional translocations including eight with a jumping behavior. In addition, six other telomeric translocations defined by banding methods, including another case of 12q translocation/i(12p), have also been jumping ones. These telomeric translocations have been de noro events and their proneness to exhibit a jumping behavior appears to be independent of the involved chromosomes, size of the translocated segments, and concomitant abnormalities.