| 1. |
- Gorunova, Ludmila, et al.
(författare)
-
Cytogenetic Analysis of 101 Giant Cell Tumors of Bone: Nonrandom Patterns of Telomeric Associations and Other Structural Aberrations
- 2009
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 48:7, s. 583-602
-
Tidskriftsartikel (refereegranskat)abstract
- Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor with metastatic potential. We performed cytogenetic analysis on 10 1 GCTB from 92 patients. Karyotypes were obtained from 95 tumors, 47 of which had clonal aberrations. The majority of the cytogenetically abnormal GCTB had multiple, up to 28 per tumor, clones. Clonal telomeric associations (tas) and other structural and numerical changes were found in about 70, 60, and 30%, respectively, of clonally abnormal tumors. Forty-seven aberrations were recurrent, of which 35 are novel. The vast majority of the recurrent aberrations were tas, confirming the important role of telomeric fusions in the development of GCTB. The frequency of tas in GCTB cultures increased with passaging, suggesting a selective advantage of tas-positive cells in vitro. The termini most frequently involved in tas were 22p, 13p, 15p, 21p, 14p, 19q, 1q, 12p, 11p, and 20q. The frequency of tas (irrespective of their clonality) was significantly higher in tumors carrying clonal changes, indicating that tas are precursors of other types of aberrations. In line with this assumption, the chromosomes preferentially involved in tas in a given tumor were also the ones most often affected by other rearrangements. We did not find the previously reported amplicon in 20q11.1, assessed by fluorescence in situ hybridization in 10 tumors. Nor did we find any association between cytogenetic features and adverse clinical outcome. Thus, local recurrences probably depend more on the adequacy of surgical treatment than on the intrinsic biology of the tumors. (C) 2009 Wiley-Liss, Inc.
|
|
| 2. |
- Guastadisegni, Maria Corsignano, et al.
(författare)
-
Bone marrow ectopic expression of a non-coding RNA in childhood T-cell acute lymphoblastic leukemia with a novel t(2;11)(q11.2;p15.1) translocation
- 2008
-
Ingår i: Molecular Cancer. - : Springer Science and Business Media LLC. - 1476-4598. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- Chromosomal translocations play a crucial role in tumorigenesis, often resulting in the formation of chimeric genes or in gene deregulation through position effects. T-cell acute lymphoblastic leukemia (T-ALL) is associated with a large number of such rearrangements. We report the ectopic expression of the 3' portion of EST DA926692 in the bone marrow of a childhood T-ALL case showing a t(2;11)(q11.2;p15.1) translocation as the sole chromosome abnormality. The breakpoints, defined at the sequence level, mapped within HPS5 ( Hermansky Pudlak syndrome 5) intron 1 at 11p15.1, and DA926692 exon 2 at 2q11.2. The translocation was accompanied by a submicroscopic inversion that brought the two genes into the same transcriptional orientation. No chimeric trancript was detected. Interestingly, Real-Time Quantitative (RQ)-PCR detected, in the patient's bone marrow, expression of a 173 bp product corresponding to the 3' portion of DA926692. Samples from four T-ALL cases with a normal karyotype and normal bone marrow used as controls were negative. It might be speculated that the juxtaposition of this genomic segment to the CpG island located upstream HPS5 activated DA92669 expression. RQ-PCR analysis showed expression positivity in 6 of 23 human tissues examined. Bioinformatic analysis excluded that this small non-coding RNA is a precursor of micro-RNA, although it is conceivable that it has a different, yet unknown, functional role. To the best of our knowledge, this is the first report, in cancer, of the activation of a small non-coding RNA as a result of a chromosomal translocation.
|
|
| 3. |
- Macchia, Gemma, et al.
(författare)
-
Rearrangements of chromosome bands 15q12-q21 are secondary to HMGA2 deregulation in conventional lipoma.
- 2014
-
Ingår i: Oncology Reports. - : Spandidos Publications. - 1791-2431 .- 1021-335X. ; 31:2, s. 807-811
-
Tidskriftsartikel (refereegranskat)abstract
- Rearrangements of chromosome arm 15q are rare but recurrent in conventional lipomas, a tumor type often showing deregulated expression of the HMGA2 gene. In order to assess whether 15q rearrangements could constitute a distinct pathogenetic mechanism, we studied seven cases of conventional lipoma that at G-banding analysis had various rearrangements of 15q12-q21. The breakpoints in 15q were mapped by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array analyses, and the status of the HMGA2 gene was evaluated by FISH and/or quantitative PCR. We found an overlapping deletion on 15q in two cases, but no recurring breakpoint among the other cases. In addition, all cases displayed rearrangement of HMGA2 at the genomic or the transcriptional level. Although 15q rearrangements sometimes are noted as the sole aberration at cytogenetic analysis of conventional lipomas, they are secondary to HMGA2 deregulation.
|
|
| 4. |
- Macchia, Gemma, et al.
(författare)
-
Ring chromosomes, breakpoint clusters, and neocentromeres in sarcomas.
- 2015
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 54:3, s. 156-167
-
Tidskriftsartikel (refereegranskat)abstract
- Gene amplification is relatively common in tumors. In certain subtypes of sarcoma, it often occurs in the form of ring and/or giant rod-shaped marker (RGM) chromosomes whose mitotic stability is frequently rescued by ectopic novel centromeres (neocentromeres). Little is known about the origin and structure of these RGM chromosomes, including how they arise, their internal organization, and which sequences underlie the neocentromeres. To address these questions, 42 sarcomas with RGM chromosomes were investigated to detect regions prone to double strand breaks and possible functional or structural constraints driving the amplification process. We found nine breakpoint cluster regions potentially involved in the genesis of RGM chromosomes, which turned out to be significantly enriched in poly-pyrimidine traits. Some of the clusters were located close to genes already known to be relevant for sarcomas, thus indicating a potential functional constraint, while others mapped to transcriptionally inactive chromatin domains enriched in heterochromatic sites. Of note, five neocentromeres were identified after analyzing 13 of the cases by fluorescent in situ hybridization. ChIP-on-chip analysis with antibodies against the centromeric protein CENP-A showed that they were a patchwork of small genomic segments derived from different chromosomes, likely joint to form a contiguous sequence during the amplification process. © 2014 Wiley Periodicals, Inc.
|
|
| 5. |
- Macchia, Gemma, et al.
(författare)
-
The hidden genomic and transcriptomic plasticity of giant marker chromosomes in cancer
- 2018
-
Ingår i: Genetics. - : Oxford University Press (OUP). - 0016-6731 .- 1943-2631. ; 208:3, s. 951-961
-
Tidskriftsartikel (refereegranskat)abstract
- Genome amplification in the form of rings or giant rod-shaped marker chromosomes (RGMs) is a common genetic alteration in soft tissue tumors. The mitotic stability of these structures is often rescued by perfectly functioning analphoid neocentromeres, which therefore significantly contribute to cancer progression. Here, we disentangled the genomic architecture of many neocentromeres stabilizing marker chromosomes in well-differentiated liposarcoma and lung sarcomatoid carcinoma samples. In cells carrying heavily rearranged RGMs, these structures were assembled as patchworks of multiple short amplified sequences, disclosing an extremely high level of complexity and definitely ruling out the existence of regions prone to neocentromere seeding. Moreover, by studying two well-differentiated liposarcoma samples derived from the onset and the recurrence of the same tumor, we documented an expansion of the neocentromeric domain that occurred during tumor progression, which reflects a strong selective pressure acting toward the improvement of the neocentromeric functionality in cancer. In lung sarcomatoid carcinoma cells we documented, extensive “centromere sliding” phenomena giving rise to multiple, closely mapping neocentromeric epialleles on separate coexisting markers occur, likely due to the instability of neocentromeres arising in cancer cells. Finally, by investigating the transcriptional activity of neocentromeres, we came across a burst of chimeric transcripts, both by extremely complex genomic rearrangements, and cis/trans-splicing events. Post-transcriptional editing events have been reported to expand and variegate the genetic repertoire of higher eukaryotes, so they might have a determining role in cancer. The increased incidence of fusion transcripts, might act as a driving force for the genomic amplification process, together with the increased transcription of oncogenes.
|
|
| 6. |
|
|
| 7. |
- Storlazzi, Tiziana, et al.
(författare)
-
A novel fusion gene, SS18L1/SSX1, in synovial sarcoma
- 2003
-
Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 37:2, s. 195-200
-
Tidskriftsartikel (refereegranskat)abstract
- Synovial sarcoma is an aggressive soft tissue tumor that is characterized cytogenetically by the t(X;18)(p11;q11) translocation, resulting in fusion between the SS18 gene on chromosome 18 and one of the SSX genes on the X chromosome. The three fusion genes that have been detected thus far, SS18/SSX1, SS18/SSX2, and SS18/SSX4, account for more than 95% of the synovial sarcomas. Because SS18/SSX fusions do not seem to occur in other tumor types, and because synovial sarcomas may sometimes be difficult to distinguish from other spindle cell tumors, molecular genetic analysis has become established as an important diagnostic tool. Upon cytogenetic analysis of a soft-tissue tumor that showed classic synovial sarcoma morphology, we detected two supernumerary marker chromosomes but no rearrangement of chromosomes X or 18. By fluorescence in situ hybridization, the marker chromosomes were shown to contain material from chromosomes X and 20, including the SSX gene cluster on the X chromosome and the SS18L1 gene, which shows strong homology with the SS18 gene, on chromosome 20. Further RT-PCR analysis and sequencing of the amplified products revealed a novel SS18L1/SSX1 fusion transcript in which nucleotide 1216 (exon 10) of SS18L1 was fused in-frame with nucleotide 422 (exon 6) of SSX1. Thus, the existence of genetic heterogeneity has to be taken into account when RT-PCR is used for the diagnosis of synovial sarcoma.
|
|
| 8. |
- Storlazzi, Tiziana, et al.
(författare)
-
Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma
- 2003
-
Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 12:18, s. 2349-2358
-
Tidskriftsartikel (refereegranskat)abstract
- The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. BBF2H7 spans more than 120 kbp genomic DNA, is composed of 12 exons and contains a 1560 bp open reading frame. It codes for a 519 amino acid protein that contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif, highly similar to that in the OASIS, CREB-H, CREB4 and CREB3 transcription factors, followed by a hydrophobic region predicted to be an alpha-helical transmembrane domain. Reverse transcription-polymerase chain reaction (RT-PCR), using FUS forward and BBF2H7 reverse primers, amplified FUS/BBF2H7 chimeric transcripts composed of the first five exons and part of exon 6 of FUS and part of exon 5 and exons 6-12 of BBF2H7. The FUS/BBF2H7 chimera codes for a protein containing the N-terminus of FUS and the B-ZIP domain and the C-terminus of BBF2H7.
|
|
| 9. |
- Storlazzi, Tiziana, et al.
(författare)
-
Ring chromosomes and low-grade gene amplification in an atypical lipomatous tumor with minimal nuclear atypia
- 2003
-
Ingår i: International Journal of Oncology. - 1019-6439. ; 23:1, s. 67-71
-
Tidskriftsartikel (refereegranskat)abstract
- Atypical lipomatous tumors (ALTs) are characterized by supernumerary ring chromosomes and/or giant marker chromosomes, which typically are composed of interspersed, amplified 12q-sequences, are C-band negative, lack a-satellite sequences, and display high copy numbers of several oncogenes, including HMGA2 (a.k.a. HMGIC) and MDM2, from the 12q13-15 region. In the present study, we report the cytogenetic and molecular genetic findings in an ALT with minimal nuclear atypia from a 16-year-old boy. At G-banding analysis, 1-3 supernumerary ring chromosomes were detected. Combined binary ratio labeling fluorescence in situ hybridization (COBRA-FISH) showed that the rings were entirely composed of material from chromosome 12, and by further FISH analysis with locus-specific probes it was revealed that they consisted of two tandemly arranged copies of the segment 12p11.2-p13.2 to 12q21.2-q23.1. Within that segment of chromosome 12, there was a small deletion including the HMGA2 locus. There was no variation in ring size and no interphase bridges could be detected, indicating that the ring chromosomes were mitotically relatively stable. The present case thus adds support to the concept that there exists a subset of ALT with limited or minimal nuclear atypia and low-level amplification of 12q sequences, further suggesting the possibility of a molecular genetic continuum between lipoma and classical examples of ALT. Furthermore, the present data strongly imply that it is the composition of the rings rather than the ring chromosome formation as such that causes the genetic instability and nuclear atypia frequently seen in ALTs.
|
|
| 10. |
- Tolomeo, Doron, et al.
(författare)
-
BL1391 : an established cell line from a human malignant peripheral nerve sheath tumor with unique genomic features
- 2021
-
Ingår i: Human Cell. - : Springer Science and Business Media LLC. - 0914-7470 .- 1749-0774. ; 34:1, s. 238-245
-
Tidskriftsartikel (refereegranskat)abstract
- Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive tumors, accounting for around 5% of all soft tissue sarcomas. A better understanding of the pathogenesis of these tumors and the development of effective treatments are needed. In this context, established tumor cell lines can be very informative, as they may be used for in-depth molecular analyses and improvement of treatment strategies. Here, we present the genomic and transcriptomic profiling analysis of a MPNST cell line (BL1391) that was spontaneously established in our laboratory from a primary tumor that had not been exposed to genotoxic treatment. This cell line shows peculiar genetic features, such as a large marker chromosome composed of high-copy number amplifications of regions from chromosomes 1 and 11 with an embedded neocentromere. Moreover, the transcriptome profiling revealed the presence of several fusion transcripts involving the CACHD1, TNMA4, MDM4, and YAP1 genes, all of which map to the amplified regions of the marker. BL1391 could be a useful tool to study genomic amplifications and neocentromere seeding in MPNSTs and to develop new therapeutic strategies.
|
|
