Molecular characterisation of the t(1;15)(p22;q22) translocation in the prostate cancer cell line LNCaP

Although chromosome translocations are well-documented recurrent events in hematological malignancies and soft tissue sarcomas, their significance in carcinomas is less clear. We report here the molecular characterization of the reciprocal translocation t(1;15)(p22;q22) in the prostate carcinoma cell line, LNCaP. The chromosome 1 breakpoint was localized to a single BAC clone, RP11-290M5, by sequential FISH analysis of clones selected from the NCBI chromosome 1 map. This was further refined to a 580-bp region by Southern blot analysis. A 2.85-kb fragment spanning the der(1) breakpoint was amplified by long-range inverse PCR. The breakpoint on chromosome 1 was shown to lie between the CYR61 and the DDAH1 genes with the der(1) junctional sequence linking the CYR61 gene to the TSPAN3 (TM4SF8) gene on chromosome 15. Confirmatory PCR and FISH mapping of the der(15) showed loss of chromosome material proximal to the breakpoint on chromosome 15, containing the PSTPIP1 and RCN2 genes. On the available evidence we conclude that this translocation does not result in an in-frame gene fusion. Comparative expressed sequence hybridization (CESH) and comparative genomic hybridization (CGH) analysis, showed relative down-regulation of gene expression surrounding the breakpoint, but no gross change in genomic copy number. Real-time quantitative RT-PCR for genes around the breakpoint supported the CESH data. Therefore, here we may have revealed a gene down-regulation mechanism associated with a chromosome translocation, either through small deletion at the breakpoint or through another means of chromosome domain related gene regulation.     

An azoospermic male with reciprocal translocation t(1;15)(q11;p11)

Summary The authors report on a case of 1;15 translocation and request contact with any colleagues who have observed similar cases.     

Genetic recombination in a chromosomal translocation t(2;8)(p11;q24) of a Burkitt's lymphoma cell line, KOBK101

We analyzed a chromosomal translocation, t(2;8)(p11;q24), in a Burkitt's lymphoma cell line, KOBK101. The translocation reciprocally occurred between a site about 150 bp upstream from the J5 segment in the Ig kappa-encoding gene on chromosome 2 and the A-rich end of an Alu repetitive element located far downstream from the c-myc gene on chromosome 8. Short segments of both parental chromosomes were deleted at the rearrangement site. A sequence related to the heptamer recognition signal for the V-J recombination of Ig genes and a topoisomerase I-recognition sequence were detected at the breakpoints. The V-J recombination occurred on both chromosome 2 and the translocated chromosome 2p- at the J3 and J4 segments, respectively. The J region on the translocated chromosomes was mutated, as compared with that on the untranslocated chromosome, while the Alu element and its upstream sequence were conserved. These results suggest the following aspects to the chromosomal translocation of this cell line. A V-J recombination seems to have occurred at the proximal end of the J4 segment first, and then the translocation took place in the region between the J4 and J5 segments. The translocation may have been mediated by the functions of topoisomerase I and the Alu repetitive sequence located at the breakpoint, although the possibility cannot be ruled out that the recombination machinery for Ig gene rearrangements functioned irregularly.     

Partial trisomy 2q and familial translocation t(2;12)(q31;q24)

Summary Report is given of a boy with trisomy of the distal part of the long arm of chromosome 2 (q31ter) due to a balanced 2/12 translocation in the mother: 46,XX,t(2;12) (q31;q24). Other phenotypically normal carriers of this balanced translocation are the patients sister and grandfather. The patient shows a variety of dysplastic signs mainly of the face.     

Novel translocation t(3;11)(p21;q24) in multiple myeloma characterised by FISH

We present a 72 year old man with multiple myeloma (MM). Cytogenetic and FISH analysis of bone marrow aspirate showed a novel translocation -der(11)t(3;11)(p21;q24). The unbalanced karyotype led to substantial partial trisomy for chromosome 3p and small partial monosomy 11q. Structural rearrangements of chromosome 3 are uncommon in MM and these are reviewed. The patient died 2 years after the diagnosis of MM was made.     

Trisomy of the distal 15q region due to familial balanced translocation t(15;16)(q24;p13) and unusual mosaicism in the mother of the proband

Clinic-cytogenetic analysis of the patient with distal 15q trisomy is presented. Proband's mother and grandmother are carriers of the balanced translocation t (15; 16) (q24; p13). Phenotypically normal proband's mother has a second cell clone with repaired marker chromosome 15 which participates in the balanced translocation of the main cell line. It is supposed possible to repair translocated human chromosomes as a result of mitotic recombination process.     

Intragenic breakpoint within RAD51L1 in a t(6;14)(p21.3;q24) of a pulmonary chondroid hamartoma

Rearrangements involving chromosome region 14q23-->q24 represent a main cytogenetic subgroup in a variety of benign solid tumors. Recently, in uterine leiomyomas containing the classical t(12;14)(q15;q23-->q24), the primary chromosome 14 target gene was identified as the protein kinase-encoding gene RAD51L1. In this report we show that RAD51L1 is also involved in the frequently occurring t(6;14) (p21;q23-->q24) in pulmonary chondroid hamartomas.     

Familial unbalanced translocation t(8;15)(p23.3;q11) with uniparental disomy in Angelman syndrome

A 29-year-old male with Angelman syndrome and an unbalanced reciprocal translocation, 45,XY,-8,-15,+der(8),t(8;15)(p23.3;q11)pat, was evaluated with DNA studies. These showed the underlying mechanism to be paternal uniparental disomy. This is the second case reported of Angelman syndrome that has resulted from a familial unbalanced reciprocal translocation.     

A novel chromosomal abnormality t (9;14)(p24;q13) in B-acute lymphoblastic leukemia

Acute lymphoblastic leukemia is a malignant disease of the bone marrow in which early lymphoid precursors proliferate and replace the normal hematopoietic cells of the marrow. We describe the clinical, morphologic, immunophenotypic and cytogenetic findings in the case of a 26-year-old man with B-lymphoblastic leukemia. Surface marker analysis revealed that they are positive for CD markers CD10, CD19, CD13, CD34, CD45 and HLA-DR, but negative for CD20, CD33, CD117 and CD11C markers. Cytogenetic analysis established a novel translocation, t (9;14)(p24;q13). Apart from this, spectral karyotyping revealed an additional translocation, t (6p; 14q). This is the first documented case of B-lymphoblastic leukemia with concurrent occurrence of both abnormalities. Further studies are needed to understand the role of this abnormality in carcinogenesis.     

Partial trisomy 15q due to maternal translocation t(7;15)(q35;14)]

Partial trisomy for the long arm of chromosome 15 was detected in a 21-year-old girl with severe growth and mental retardation. A balanced reciprocal translocation - t(7;15)(q35;q14) - is present in the mother.     

Familial translocation t(10;21)(q22;q22)

Summary A family is described with a translocation t(10;21)(q22;q22) transmitted through three generations. This family was studied for the apparition of several miscarriages and two sisters with multiple malformations. Both children had a probably partial trisomy of chromosome 10 and a monosomy of chromosome 21 due to a maternal adjacent-2 meiotic segregation.     

Sotos syndrome with a balanced reciprocal translocation t(2;12)(q33.3;q15)

A balanced reciprocal translocation, 46,XY, t(2;12), was detected in a male infant who had the characteristic features of Sotos syndrome. His father's karyotype was normal, but his mother and an older brother had the same chromosomal abnormality without a history or clinical features of Sotos syndrome.     

Novel variant Ph translocation t(9;22;11)(q34;q11.2;p15)inv(9)(p13q34) in chronic myeloid leukemia involving a one-step mechanism

Chronic myeloid leukemia (CML) is a clonal malignant disorder of a pluripotent hematopoietic stem cell characterized by the presence of a Philadelphia (Ph) chromosome. Less than 10% of patients present variant Ph chromosomes involving 1 or more additional chromosomes, other than chromosomes 9 and 22, with uncertain prognosis. There are mainly 1- or 2-step mechanisms proposed to explain the genesis of variant Ph chromosomes depending on whether the involved chromosomes are simultaneously broken and rejoined or if a standard t(9;22) occurs first. By combined standard cytogenetic and FISH analysis we detected a novel variant Ph translocation among chromosomes 9, 11 and 22 in a patient with CML without progression to an accelerated phase of the disease after 7 years, with the derivative chromosome 9 also having an acquired pericentric inversion. This novel case illustrates the use of FISH in metaphase to confirm a new rearrangement not previously described in variant Ph formation and that the present karyotype could have originated by a 1-step mechanism with 4 simultaneous breakages without deletion of ABL1.     

Partial trisomy 2q and familial translocation t(2;18)(q31;p11)

Summary This report describes a malformed infant with distal 2q trisomy/ distal 18p monosomy due to adjacent segregation of a familial t(2;18). The rearrangement was present in four generations, and linkage studies were performed.     

Congenital hyperthyroidism with reciprocal translocation t(1;17)(q25;q21)

Summary The authors report a case of 1;17 translocation and request contact with colleagues who have observed similar cases.     

A maternal inherited translocation t(1;22)(q11;p11) in two infertile brothers

We report two infertile brothers presenting with azoospermia and oligozoospermia. Cytogenetic studies using G-banding and FISH analysis on lymphocyte cultures revealed an autosomal balanced reciprocal translocation t(1;22)(q11;p11) in both males. The same translocation was found in their mother, but not in a third fertile brother and maternal uncle suggesting that this translocation might compromise the male but not the female gametogenesis in this family.     

The position of t(11;22)(q23;q11) constitutional translocation breakpoint is conserved among its carriers

The t(11;22)(q23;q11) translocation is the most common recurrent balanced translocation described in humans. Carriers are phenotypically normal and often go undetected until diagnosis as a result of infertility investigations or following the birth of chromosomally unbalanced offspring. Efficient diagnostics of t(11;22) is important for children born to carriers of the translocation and for prenatal and pre-implantation diagnosis. The translocation breakpoint on chromosome 22 is located within a region containing low copy repeats, and this site is one of the last unfilled gaps in the sequence of this chromosome. This autosome harbors multiple other low copy repeats, which have been entirely sequenced. We report a combined sequencing and fiber FISH breakpoint characterization in five translocation carriers. From one carrier a cosmid library was constructed, and two chimeric cosmids (cos4_der11 and cos6_der22) were sequenced, which showed that strong palindromes (or inverted repeats) occur on both chromosomes. The translocation breakpoints occur at the tip of both inverted repeats. The palindrome on chromosomes 22 and 11 is composed of 852 and 166 bases, respectively. Four additional carriers were studied using fiber FISH with a resolution limit of 2 kb. Analysis of breakpoints on the DNA sequence level, or at the level of fiber FISH, indicate that they occur at the same position on both chromosomes in all five carriers. Using cos6_der22, PAC 158L19 and BAC 3009A19, we demonstrate that FISH is an attractive alternative in molecular diagnostics of t(11;22), as PCR assays are not reliable, due to the presence of numerous copies of low copy repeats.     

Identification of sequence motifs at the breakpoint junctions in three t(1;9)(p36.3;q34) and delineation of mechanisms involved in generating balanced translocations

Although approximately 1 in 500 individuals carries a reciprocal translocation, little is known about the mechanisms that result in their formation. We analyzed the sequences surrounding the breakpoints in three unbalanced translocations of 1p and 9q, all of which were designated t(1;9)(p36.3;q34), to investigate the presence of sequence motifs that might mediate nonhomologous end joining (NHEJ). The breakpoint regions were unique in all individuals. Two of three translocations demonstrated insertions and duplications at the junctions, suggesting NHEJ in the formation of the rearrangements. No homology was identified in the breakpoint regions, further supporting NHEJ. We found translin motifs at the breakpoint junctions, suggesting the involvement of translin in the joining of the broken chromosome ends. We propose a model for balanced translocation formation in humans similar to transposition in bacteria, in which staggered nicks are repaired resulting in duplications and insertions at the translocation breakpoints.