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PubMed1999

Testing the nonrandomness of chromosomal breakpoints using highest observed breakages.

To determine whether a chromosomal band is a fragile site rather than a spontaneous breakpoint, an essential step is to test the nonrandomness of breakage at the region. In this paper, the nonapplicability of the testing procedure introduced by Bohm et al. is discussed, and a new detection procedure is proposed. This new procedure considers the relations of one site with the others, and can be applied to tests of the nonrandomness of breakpoints under either the proportional probability model, or the equiprobability model. A data set for Chinese patients with colorectal carcinoma is analyzed as an illustration of the proposed method.

China↗
PubMed1989

Childhood acute lymphoblastic leukemia with chromosomal breakpoints at 11q23.

Twenty-one (5.7%) of 368 cases of acute lymphoblastic leukemia (ALL), studied fully for karyotype and immunophenotype, had breakpoints in the q23 region of chromosome 11. This abnormality resulted from reciprocal translocation in 17 cases [with chromosomes 4 (n = 5), 10 (n = 2), and variable chromosomes (n = 10)], from deletions in three cases, and from a duplication in one case. The 17 children with 11q23 translocations had higher leukocyte counts (P less than .01) and were more likely to be black (P less than .01) and younger (P = .08) as compared with each of the following non-11q23 translocation groups: t(1;19), t(9;22), random translocations, and cases without translocations. Event-free survival at 3 years for the 11q23 translocation group did not differ significantly from that of the t(1;19), t(9;22), or random translocation groups. Leukemic cells from ten of the 21 patients with an 11q23 structural chromosomal abnormality had an immunophenotype indicative of B-lineage ALL (HLA-DR+, CD19+, CD2-, CD3-); this was confirmed by the presence of rearranged immunoglobulin heavy-chain genes in seven cases. In eight of these ten B-lineage cases, the blasts were negative for expression of the CD10 antigen, indicating a primitive stage of B-cell development. Four cases were classified as T-cell ALL, and seven others were characterized by blasts that failed to react with our panel of lineage-associated monoclonal antibodies (MoAbs). Myeloid antigens were expressed by leukemic cells in three of the cases that were tested. The initial clinical features associated with translocations involving the 11q23 chromosomal region may define a distinct subtype of ALL. Whether the constellation of findings relates to a breakpoint at 11q23 per se or to the specific translocation will require further study.

Chromosome Aberrations↗
PubMed2003

Fine mapping of an isodicentric Y chromosomal breakpoint from a schizophrenic patient.

We report on a male schizophrenic patient who carried an isodicentric Y chromosome [idic(Y)] with a mosaic karyotype [mos 45,X/46,X,idic(Y)(q11)]. Although a potential association between sex chromosome abnormalities and a susceptibility to psychoses has been documented, there has only been one previous report of idic(Y) coincident with schizophrenia. The [45,X] karyotype is known to be associated with Turner syndrome (TS), but our patient lacked most of the phenotypic features of TS, except for short stature. To define the precise position of the breakpoint on the patient's abnormal Y chromosome, we carried out polymerase chain reaction (PCR) analysis, using primers for 15 marker loci along the chromosome. The breakpoint was localized to between the marker loci sY118 and sY119 on Yq in the 5M interval of the deletion map. This position represents the most centromeric breakpoint recorded for idic(Y). We cannot exclude the possibility that the development of schizophrenia is unrelated to the Y chromosome abnormality in this patient but we hope that this study will stimulate further cytogenetic and molecular genetic analyses of Y chromosome regions that may influence psychiatric traits.

Aged↗
PubMed1988

Thermostable DNA polymerase chain amplification of t(14;18) chromosome breakpoints and detection of minimal residual disease.

Achieving the capacity to detect minimal numbers of neoplastic cells is a major cancer diagnostic challenge. Chromosomal translocations such as the t(14;18)(q32;q21) found in follicular and some nonfollicular lymphomas provide a tumor-specific molecular marker. The 14;18 breakpoints are focused at one of six immunoglobulin heavy chain joining (JH) regions on chromosome 14 and a small major breakpoint region (MBR) of the BCL2 gene on chromosome 18. We utilized universal oligonucleotide primers of a region 5' to the BCL2 MBR and at the 3' end of JH segments to initiate a DNA polymerase chain reaction that amplified these BCL2-JH junctures. Use of thermostable DNA polymerase enabled annealing and synthesis steps at temperatures approaching the melting point of the primers, providing a sensitive and specific assay capable of detecting 1 lymphoma cell in 10(6) normal cells. This technique identified the subclinical presence of leukemic cells in all seven patients examined, including two in clinical remission. It also assessed the effectiveness of protocols designed to purge malignant cells from marrow. Moreover, this approach enabled the rapid DNA sequencing of chromosomal breakpoints without their molecular cloning. This assay markedly refines the capacity to detect minimal residual disease and should improve the ability to determine the stage of disease, stratify treatment, and evaluate therapy.

Bacterial Proteins↗
PubMed2001

Analysis of the V(D)J recombination efficiency at lymphoid chromosomal translocation breakpoints.

Chromosomal translocations and deletions are among the major events that initiate neoplasia. For lymphoid chromosomal translocations, misrecognition by the RAG (recombination activating gene) complex of V(D)J recombination is one contributing factor that has long been proposed. The chromosomal translocations involving LMO2 (t(11;14)(p13;q11)), Ttg-1 (t(11;14)(p15;q11)), and Hox11 (t(10;14)(q24;q11)) are among the clearest examples in which it appears that a D or J segment has synapsed with an adventitious heptamer/nonamer at a gene outside of one of the antigen receptor loci. The interstitial deletion at 1p32 involving SIL (SCL-interrupting locus)/SCL (stem cell leukemia) is a case involving two non-V(D)J sites that have been suggested to be V(D)J recombination mistakes. Here we have used our human extrachromosomal substrate assay to formally test the hypothesis that these regions are V(D)J recombination misrecognition sites and, more importantly, to quantify their efficiency as V(D)J recombination targets within the cell. We find that the LMO2 fragile site functions as a 12-signal at an efficiency that is only 27-fold lower than that of a consensus 12-signal. The Ttg-1 site functions as a 23-signal at an efficiency 530-fold lower than that of a consensus 23-signal. Hox11 failed to undergo recombination as a 12- or 23-signal and was at least 20,000-fold less efficient than consensus signals. SIL has been predicted to function as a 12-signal and SCL as a 23-signal. However, we find that SIL actually functions as a 23-signal. These results provide a formal demonstration that certain chromosomal fragile sites can serve as RAG complex targets, and they determine whether these sites function as 12- versus 23-signals. These results quantify one of the three major factors that determine the frequency of these translocations in T-cell acute lymphocytic leukemia.

Adaptor Proteins, Signal Transducing↗
PubMed1993

A method for testing the nonrandomness of chromosomal breakpoints.

Testing the nonrandomness of breakage at a chromosome band is an essential step fo identifying a fragile site. In this paper, we propose a method derived by using the relationship between the binomial and F distributions for testing nonrandomness. The method is simple in calculation. It was applied to the detection of fragile sites for Chinese patients with colorectal carcinoma.

Carcinoma↗
PubMed2003

Genomic characterization of the chromosomal breakpoints of t(4;14) of multiple myeloma suggests more than one possible aetiological mechanism.

Using FISH-based techniques, rearrangements of the immunoglobulin heavy-chain (IgH) locus at 14q32 have been found in the majority of cases of multiple myeloma (MM). Some of these IgH translocations are recurrent and we have characterized the genomic breakpoints of seven t(4;14) translocations from MM patients, using a combination of vectorette and conventional polymerase chain reaction methods, the aim being to understand the molecular mechanism leading to MM. Conventionally, the chromosome 14q32 breakpoints in these reciprocal translocations are believed to be located in the IgH mu switch (S) region and a further downstream S region with deletion of intervening DNA occurring as a result of aberrant class switch recombination (CSR); this was seen in five of the cases analysed. However, in two patients it was possible to demonstrate that the rearranged hybrid switch region sequence was joined to DNA from chromosome 4p16, suggesting that IgH translocations can occur in B cells that have already undergone legitimate CSR. The complex nature of these rearrangements leads us to speculate that primary IgH translocations may occur at different time points in the development in MM plasma cells, either at the time of physiological CSR or at a later stage, possibly involving a different mechanism.

B-Lymphocytes↗
PubMed2000

Physical map of a 1.5 mb region on 12p11.2 harbouring a synpolydactyly associated chromosomal breakpoint.

Synpolydactyly (SPD) is a rare malformation of the distal limbs known to be caused by mutations in HOXD13. We have previously described a complex form of SPD associated with synostoses in three members of a Belgian family, which co-segregates with a t(12;22)(p11.2;q13.3) chromosomal translocation. The chromosome 12 breakpoint of this translocation maps to 12p11.2 between markers D12S1034 and D12S1596. Here we show that a mutation in the HOXD13 gene is not responsible for the phenotype, and present a physical map of the region around the 12p11.2 breakpoint. Starting from D12S1034 and D12S1596, we have established a contig approximately 1.5 Mb in length, containing 13 YAC clones, 16 BAC clones, and 11 cosmid clones. FISH analysis shows that cosmid LL12NCO1-149H4 maps across the breakpoint, and Southern blot experiments using fragments of this cosmid as probes identify a rearranged BamHI fragment in the patients carrying the translocation. A search for expressed sequences within the contig have so far revealed one CpG island, seven anonymous ESTs and three previously characterised genes, DAD-R, KRAG and HT21, all of which were found not to be directly disrupted by the translocation. The gene represented by EST R72964 was found to be disrupted by the translocation. These findings lay the groundwork for further efforts to characterise a gene critical for normal distal limb development that is perturbed by this translocation.

Base Sequence↗
PubMed2002

Molecular cytogenetic mapping of recurrent chromosomal breakpoints in tenosynovial giant cell tumors.

Tenosynovial giant cell tumor (TGCT) is the most common benign tumor of synovium and tendon sheath. Cytogenetic data indicate that 1p11-13 is the region most frequently involved in structural rearrangements. With the aim of eventually identifying the genes associated with TGCT development, we have investigated 1p11-13 breakpoints using fluorescence in situ hybridization (FISH) analysis, with a panel of yeast artificial chromosome (YAC) probes covering 1p11-21. Twenty-six tumors were analyzed by G-banding, and 24 of these showed a breakpoint in 1p11-13. The cytogenetic findings add to previous observations that, among a variety of translocations involving 1p11-13, chromosome 2 is the most common translocation partner, with a breakpoint in 2q35-37. This aberration was found in eight cases. Other recurrent translocation partners, found in two or three cases, were 5q22-31, 11q11-12, and 8q21-22. Material from 21 tumors was available for FISH analysis, which revealed that the breakpoints clustered to one region spanned by two YAC probes, 914F6 and 885F12 located in 1p13.2, in 18 cases. Bacterial artificial chromosome probes were used to map the recurrent breakpoint on chromosome 2. In four of seven cases there was a breakpoint within the sequence covered by probe 260J21, where the RDC1 gene is located, a gene reported to fuse with HMGIC in lipomas with a 2;12 translocation.

Adolescent↗
PubMed2003

The donor chromosome breakpoint for a jumping translocation is associated with large low-copy repeats in 21q21.3.

Jumping translocations (JTs) are very rare chromosome aberrations, usually identified in tumors. We report a constitutional JT between donor chromosome 21q21.3-->qter and recipients 13qter and 18qter, resulting in an approximately 15.5-Mb proximal deletion 21q in a girl with mild developmental delay and minor dysmorphic features. Using fluorescence in situ hybridization (FISH) studies, we identified an approximately 550-kb complex inter- and intra-chromosomal low-copy repeat (LCR) adjacent to the 21q21.3 translocation breakpoint. On the recipient chromosomes 13qter and 18qter, the telomeric sequences TTAGGG were retained. Genotyping revealed that the deletion was of maternal origin. We propose that genome architecture involving LCRs may be a major mechanism responsible for the origin of jumping translocations.

Child↗
PubMed1998

The t(2;3)(q21;q27) translocation in non-Hodgkin's lymphoma displays BCL6 mutations in the 5' regulatory region and chromosomal breakpoints distant from the gene.

The BCL6 gene, mapped at the chromosomal band 3q27, encodes a POZ/Zinc finger transcription repressor protein. It is frequently activated in Non-Hodgkin's lymphomas (NHL) by translocations with breakpoints clustering in the 5' major breakpoint region (MBR) as well as by mutations in the same region. The translocations lead to BCL6 activation by substitution of promoters of rearranging genes derived from the reciprocal chromosomal partners such as IG. We report the molecular genetic analysis of a novel t(2;3)(q21;q27) translocation subset in NHL comprising three cases without apparent BCL6 involvement in the translocation. Southern blot analysis of tumor DNAs utilizing BCL6 MBR probes revealed no rearrangement in two cases. Two rearranged bands in the third case resulted from a deletion in one allele and a mutation in the other allele. Southern blot analysis of DNA from one of the two tumors without BCL6 rearrangement, using a probe derived from the recently identified alternative breakpoint region (ABR), showed a rearrangement. The ABR is located 200-270 kb telomeric to MBR. Mutations were identified in the previously reported hypermutable region of BCL6 in all three tumors. In one, the mutant allele alone was found to be expressed by RT-PCR analysis of RNA. These results demonstrate the presence of 3q27 translocation breakpoints at a distance from BCL6 suggesting distant breaks that deregulate the gene or involvement of other genes that may be subject to rearrangement.

Alleles↗
PubMed1988

Fragile sites, cancer chromosome breakpoints, and oncogenes all cluster in light G bands.

Fragile sites tend to be bands where breaks occur in cancer chromosome rearrangements that can involve oncogenes. The locations of fragile sites, cancer breakpoints, and oncogenes were therefore charted. All were predominantly in light G bands. Specifically, 78 of 89 (88%) fragile sites were in light G bands including the large group of common fragile sites inducible with aphidicolin (p less than 0.001). Of 61 cancer breakpoints, 50 (82%) were in light bands including translocation breakpoints (p less than 0.001). Thirteen of 14 (93%) oncogenes localized to light bands. The sharing of chromosome bands can stem from a biologically meaningful relationship, as between cancer breakpoints and oncogenes. Joint occupancy of chromosome bands can also reflect independent reasons to be in the same sector of the genome. Thus, fragile sites may well be in light bands because they are associated with active genes. This clearly does not rule out a biologic relationship between specific fragile sites and specific cancer breakpoints.

Chromosome Banding↗
PubMed1997

Spontaneous DNA lesions poison human topoisomerase IIalpha and stimulate cleavage proximal to leukemic 11q23 chromosomal breakpoints.

Topoisomerase II-targeted drugs, such as etoposide, "poison" this enzyme and kill cells by increasing levels of covalent topoisomerase II-cleaved DNA complexes. In spite of the success of this drug in the treatment of human cancers, a significant proportion of patients treated with etoposide eventually develop secondary leukemias that are characterized by translocations at chromosome band 11q23. Since similar translocations are associated with primary leukemias in previously untreated infants, we questioned whether they could also be triggered by the actions of "endogenous topoisomerase II poisons". Recent studies, which demonstrated that several forms of spontaneous DNA damage stimulate cleavage mediated by Drosophila topoisomerase II, suggest that DNA lesions may act as these endogenous poisons. Therefore, to determine whether the ability to recognize spontaneous DNA damage has been conserved from this lower eukaryote to mammalian species, the effects of apurinic sites, apyrimidinic sites, and deaminated cytosine residues on human topoisomerase IIalpha were assessed. All three lesions were potent poisons of the human enzyme and stimulated cleavage when located within the four-base overhang generated by enzyme-mediated DNA scission. Furthermore, these lesions increased levels of cleavage at five sites proximal to 11q23 translocation breakpoints and did so with an efficacy that was comparable to or greater than that of therapeutic concentrations of etoposide. Although the physiological relevance of these findings has yet to be established, they suggest a potential role for endogenous topoisomerase II poisons in the initiation of leukemic chromosomal breakpoints.

Base Sequence↗
PubMed1995

Localization of chromosome breakpoints induced by AluI and BamHI in Chinese hamster ovary cells treated in the G1 phase of the cell cycle.

Intact Chinese hamster ovary cells were exposed to the restriction endonucleases (REs) AluI or BamHI. In metaphase spreads from these cells, 300 breakpoints per RE were localized in G-banded chromosome type aberrations (dicentrics, translocations, rings, terminal and interstitial deletions). The majority of breakpoints induced by both REs were localized in G-light bands and showed a similar distribution of breakpoint clusters. RE digestion of metaphase spreads with AluI induced C-banding, and with BamHI G-banding. The data indicate that nuclease sensitive sites associated with active genes are mainly responsible for the distribution of breakpoints.

Animals↗
PubMed1995

Characterisation of the chromosome breakpoints in a patient with a constitutional translocation t(1;17)(p36.31-p36.13;q11.2-q12) and neuroblastoma.

Cytogenetic and molecular studies in neuroblastoma suggest the presence of a tumour suppressor gene at the distal chromosome band 1p36. Previously, we hypothesised that a constitutional translocation involving the region 1p36 [t(1;17)(p36;q12-q21)] in a patient with neuroblastoma predisposed him to tumour development. Here we report the molecular delineation of the translocation breakpoints. Somatic cell hybrids containing the derivative chromosomes were used to determine the position of chromosome 1p and 17q DNA probes respective to the breakpoints using fluorescence in situ hybridisation. The 1p breakpoint was localised between the PND and D1S56 loci. The chromosome 17q breakpoint is flanked by NF1 and SCYA7, as proximal and distal marker, respectively. We redefined the translocation as t(1;17)(p36.31-13;q11.2-q12). The identification of flanking markers of the breakpoints is a prerequisite for breakpoint cloning and identification of a putative neuroblastoma suppressor gene.

Chromosome Mapping↗
PubMed2000

Cloning, sequencing, and analysis of inv8 chromosome breakpoints associated with recombinant 8 syndrome.

Rec8 syndrome (also known as "recombinant 8 syndrome" and "San Luis Valley syndrome") is a chromosomal disorder found in individuals of Hispanic descent with ancestry from the San Luis Valley of southern Colorado and northern New Mexico. Affected individuals typically have mental retardation, congenital heart defects, seizures, a characteristic facial appearance, and other manifestations. The recombinant chromosome is rec(8)dup(8q)inv(8)(p23.1q22.1), and is derived from a parental pericentric inversion, inv(8)(p23.1q22.1). Here we report on the cloning, sequencing, and characterization of the 8p23.1 and 8q22 breakpoints from the inversion 8 chromosome associated with Rec8 syndrome. Analysis of the breakpoint regions indicates that they are highly repetitive. Of 6 kb surrounding the 8p23.1 breakpoint, 75% consists of repetitive gene family members-including Alu, LINE, and LTR elements-and the inversion took place in a small single-copy region flanked by repetitive elements. Analysis of 3.7 kb surrounding the 8q22 breakpoint region reveals that it is 99% repetitive and contains multiple LTR elements, and that the 8q inversion site is within one of the LTR elements.

Abnormalities, Multiple↗
PubMed2001

5q11, 8p11, and 10q22 are recurrent chromosomal breakpoints in prostate cancer cell lines.

Prostate cancer cell lines have been widely used as model systems characterizing pathogenetic, functional, and therapeutic aspects of prostate cancer development. However, their chromosomal compositions are poorly characterized. In this study, five prostate cancer cell lines-TSU-Pr1, JCA-1, NCI-H660, ALVA-31, and PPC-1-were investigated by G-banding, comparative genomic hybridization (CGH), and spectral karyotyping. The results were combined with our previous findings in the prostate cancer cell lines PC-3, DU145, and LNCaP. By comparative genomic hybridization (CGH), the most frequent losses were observed at 13q, 8p, 9p, and 4q, whereas gains were most commonly seen at 8q, 10q, and 18p. The composite karyotypes were characterized by multiple numerical and structural chromosomal aberrations. Recurrent breakpoints at 5q11, 8p11, and 10q22 were observed to participate in deletion and translocation events in five of the cell lines, suggesting the importance of tumor suppressor and/or oncogenes in these regions. ALVA-31 and PPC-1 shared nine identical derivative chromosomes, two of which have also been detected in PC-3. In addition, the identification of the same homozygous deletion at D10S541 and of an identical TP53 gene mutation in all three cell lines suggests a common origin of these cell lines.

Chromosome Breakage↗