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Nils Mandahl - One of the best experts on this subject based on the ideXlab platform.
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integrative genome and transcriptome analyses reveal two distinct types of Ring chromosome in soft tissue sarcomas
Human Molecular Genetics, 2014Co-Authors: Karolin Hansen Nord, Nils Mandahl, Fredrik Vult Von Steyern, Gemma Macchia, Johnbosco Tayebwa, Jenny Nilsson, Otte Brosjo, Fredrik MertensAbstract:Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of Ring Chromosomes. Such structures are mitotically unstable and duRing tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many Ring-containing tumors remains poorly characterized. Ring Chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization, global genomic copy number and gene expression data on Ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of Ring chromosome: MDM2-positive and MDM2-negative Rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative Rings commonly show complete loss of either CDKN2A or RB1-both known to be important for genome integrity. Sarcomas with MDM2-positive Rings instead show co-amplification of a variety of potential driver oncogenes. More than one hundred different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets. (Less)
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fusion of the fus and creb3l2 genes in a supernumerary Ring chromosome in low grade fibromyxoid sarcoma
Cancer Genetics and Cytogenetics, 2010Co-Authors: Hammurabi Bartuma, Henryk A Domanski, Nils Mandahl, Emely Moller, Anna Collin, Fredrik Vult Von Steyern, Fredrik MertensAbstract:Low-grade fibromyxoid sarcoma (LGFMS) is a rare, low-grade malignant soft tissue tumor that is often mistaken for either benign or more malignant tumor types. Commonly, this tumor affects young adults and typically arises in the deep proximal extremities or trunk with frequent recurrences and can metastasize to the lungs many years later. Most cases have a recurrent balanced translocation involving Chromosomes 7 and 16, t(7;16)(q32-34;p11), which leads to the fusion of the FUS and CREB3L2 genes. However, supernumerary Ring Chromosomes have been identified in a subset of FUS/CREB3L2-positive LGFMS, but it has not yet been formally demonstrated that such Ring Chromosomes harbor the FUS/CREB3L2 fusion gene. Here, we report the genetic findings of a supernumerary Ring chromosome from an LGFMS from a 77-year-old man. Chromosome banding analysis revealed a supernumerary Ring chromosome, and further studies with fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the Ring contained material from Chromosomes 7 and 16, that the FUS gene was present in two rearranged copies, and that it expressed the FUS/CREB3L2 fusion gene. Moreover, an assessment of previously reported cases showed that tumors with Ring Chromosomes relapsed more often than tumors with a balanced t(7;16), suggesting that Ring formation in LGFMS is correlated with tumor progression.
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genomic profiling of bone and soft tissue tumors with supernumerary Ring Chromosomes using tiling resolution bacterial artificial chromosome microarrays
Oncogene, 2006Co-Authors: Markus Heidenblad, Fredrik Mertens, Mattias Hoglund, Karolin H Hallor, Johan Staaf, Goran Jonsson, Ake Borg, Nils MandahlAbstract:Ring Chromosomes and/or giant marker Chromosomes have been observed in a variety of human tumor types, but they are particularly common in a subgroup of mesenchymal tumors of low-grade or borderline malignancy. These Rings and markers have been shown to contain amplified material predominantly from 12q13–15, but also sequences from other Chromosomes. Such amplified sequences were mapped in detail by genome-wide array comparative genomic hybridization in Ring-containing tumor samples from soft tissue (n=15) and bone (n=6), using tiling resolution microarrays, encompassing 32 433 bacterial artificial chromosome clones. The DNA copy number profiles revealed multiple amplification targets, in many cases highly discontinuous, leading to delineation of large numbers of very small amplicons. A total number of 356 (median size: 0.64 Mb) amplicons were seen in the soft tissue tumors and 90 (median size: 1.19 Mb) in the bone tumors. Notably, more than 40% of all amplicons in both soft tissue and bone tumors were mapped to chromosome 12, and at least one of the previously reported recurrent amplifications in 12q13.3–14.1 and 12q15.1, including SAS and CDK4, and MDM2, respectively, were present in 85% of the soft tissue tumors and in all of the bone tumors. Although chromosome 12 was the only chromosome displaying recurrent amplification in the bone tumors, the soft tissue tumors frequently showed recurrent amplicons mapping to other Chromosomes, that is, 1p32, 1q23–24, 3p11–12, 6q24–25 and 20q11–12. Of particular interest, amplicons containing genes involved in the c-jun NH2-terminal kinase/mitogen-activated protein kinase pathway, that is, JUN in 1p32 and MAP3K7IP2 (TAB2) in 6q24–25, were found to be independently amplified in eight of 11 cases with 12q amplification, providing strong support for the notion that aberrant expression of this pathway is an important step in the dedifferentiation of liposarcomas.
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Ring Chromosomes and low grade gene amplification in an atypical lipomatous tumor with minimal nuclear atypia
International Journal of Oncology, 2003Co-Authors: Clelia Tiziana Storlazzi, Henryk A Domanski, Fredrik Mertens, Christopher D M Fletcher, Joop Wiegant, Nils MandahlAbstract: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. (Less)
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differentially amplified chromosome 12 sequences in low and high grade osteosarcoma
Genes Chromosomes and Cancer, 2002Co-Authors: David Gisselsson, Henryk A Domanski, Fredrik Mertens, Paola Dal Cin, Eva Palsson, Mattias Hoglund, Nikos Pandis, Raphael Sciot, Julia A Bridge, Nils MandahlAbstract:Most osteosarcomas are highly aggressive malignancies characterized by a complex pattern of chromosome abnormalities. However, a subgroup of low-grade, parosteal tumors exhibits a relatively simple aberration pattern dominated by Ring Chromosomes carrying amplified material from chromosome 12. To assess whether sequences from this chromosome were differentially amplified in low- and high-grade osteosarcomas, copy numbers of the CCND2, ETV6, KRAS2, and D12S85 regions in 12p and the MDM2 region in 12q were evaluated by interphase or metaphase fluorescence in situ hybridization (FISH) in 24 osteosarcomas. Amplification of MDM2 was detected in all five low-grade and four high-grade osteosarcomas, all of which showed Ring Chromosomes. An overrepresentation of 12p sequences was found in 1/5 low-grade and in 9/19 high-grade tumors. Multicolor single-copy FISH analysis of metaphase cells from six high-grade tumors showed that extra 12p material either occurred together with MDM2 in Ring Chromosomes or was scattered over the genome as a result of complex structural rearrangements. Most tumors (8/10) not containing amplification of the assessed chromosome 12 loci exhibited a nondiploid pattern at evaluation with probes for centromeric alpha satellite sequences. These findings indicate that gain of sequences from the short arm of chromosome 12 could be a possible genetic pathway in the development of aggressive osteosarcoma.
Fredrik Mertens - One of the best experts on this subject based on the ideXlab platform.
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integrative genome and transcriptome analyses reveal two distinct types of Ring chromosome in soft tissue sarcomas
Human Molecular Genetics, 2014Co-Authors: Karolin Hansen Nord, Nils Mandahl, Fredrik Vult Von Steyern, Gemma Macchia, Johnbosco Tayebwa, Jenny Nilsson, Otte Brosjo, Fredrik MertensAbstract:Gene amplification is a common phenomenon in malignant neoplasms of all types. One mechanism behind increased gene copy number is the formation of Ring Chromosomes. Such structures are mitotically unstable and duRing tumor progression they accumulate material from many different parts of the genome. Hence, their content varies considerably between and within tumors. Partly due to this extensive variation, the genetic content of many Ring-containing tumors remains poorly characterized. Ring Chromosomes are particularly prevalent in specific subtypes of sarcoma. Here, we have combined fluorescence in situ hybridization, global genomic copy number and gene expression data on Ring-containing soft tissue sarcomas and show that they harbor two fundamentally different types of Ring chromosome: MDM2-positive and MDM2-negative Rings. While the former are often found in an otherwise normal chromosome complement, the latter seem to arise in the context of general chromosomal instability. In line with this, sarcomas with MDM2-negative Rings commonly show complete loss of either CDKN2A or RB1-both known to be important for genome integrity. Sarcomas with MDM2-positive Rings instead show co-amplification of a variety of potential driver oncogenes. More than one hundred different genes were found to be involved, many of which are known to induce cell growth, promote proliferation or inhibit apoptosis. Several of the amplified and overexpressed genes constitute potential drug targets. (Less)
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fusion of the fus and creb3l2 genes in a supernumerary Ring chromosome in low grade fibromyxoid sarcoma
Cancer Genetics and Cytogenetics, 2010Co-Authors: Hammurabi Bartuma, Henryk A Domanski, Nils Mandahl, Emely Moller, Anna Collin, Fredrik Vult Von Steyern, Fredrik MertensAbstract:Low-grade fibromyxoid sarcoma (LGFMS) is a rare, low-grade malignant soft tissue tumor that is often mistaken for either benign or more malignant tumor types. Commonly, this tumor affects young adults and typically arises in the deep proximal extremities or trunk with frequent recurrences and can metastasize to the lungs many years later. Most cases have a recurrent balanced translocation involving Chromosomes 7 and 16, t(7;16)(q32-34;p11), which leads to the fusion of the FUS and CREB3L2 genes. However, supernumerary Ring Chromosomes have been identified in a subset of FUS/CREB3L2-positive LGFMS, but it has not yet been formally demonstrated that such Ring Chromosomes harbor the FUS/CREB3L2 fusion gene. Here, we report the genetic findings of a supernumerary Ring chromosome from an LGFMS from a 77-year-old man. Chromosome banding analysis revealed a supernumerary Ring chromosome, and further studies with fluorescence in situ hybridization and reverse transcriptase-polymerase chain reaction (RT-PCR) showed that the Ring contained material from Chromosomes 7 and 16, that the FUS gene was present in two rearranged copies, and that it expressed the FUS/CREB3L2 fusion gene. Moreover, an assessment of previously reported cases showed that tumors with Ring Chromosomes relapsed more often than tumors with a balanced t(7;16), suggesting that Ring formation in LGFMS is correlated with tumor progression.
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deep seated ordinary and atypical lipomas histopathology cytogenetics clinical features and outcome in 215 tumours of the extremity and trunk wall
Journal of Bone and Joint Surgery-british Volume, 2008Co-Authors: V Billing, Henryk A Domanski, Fredrik Mertens, Anders RydholmAbstract:Deep-seated lipomas are often atypical histologically and are considered by some to have a high risk of recurrence after excision. We reviewed 215 deep-seated lipomas of the extremities and trunk wall with reference to histology, cytogenetics, clinical features and local recurrence. We classified tumours with atypical features and/or Ring Chromosomes as atypical lipomas. These were more common in men, larger than ordinary lipomas and more often located in the upper leg. The annual incidence was estimated as ten per million inhabitants and the ratio of atypical to ordinary lipomas was 1:3. In total, six tumours (3%), recurred locally after a median of eight years (1 to 16); of these, four were classified as atypical. The low recurrence rate of deep-seated lipomas of the extremity or trunk wall, irrespective of histological subtype, implies that if surgery is indicated, the tumour may be shelled out, that atypical lipomas in these locations do not deserve the designation well-differentiated liposarcoma, and that routine review after surgery is not required.
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genomic profiling of bone and soft tissue tumors with supernumerary Ring Chromosomes using tiling resolution bacterial artificial chromosome microarrays
Oncogene, 2006Co-Authors: Markus Heidenblad, Fredrik Mertens, Mattias Hoglund, Karolin H Hallor, Johan Staaf, Goran Jonsson, Ake Borg, Nils MandahlAbstract:Ring Chromosomes and/or giant marker Chromosomes have been observed in a variety of human tumor types, but they are particularly common in a subgroup of mesenchymal tumors of low-grade or borderline malignancy. These Rings and markers have been shown to contain amplified material predominantly from 12q13–15, but also sequences from other Chromosomes. Such amplified sequences were mapped in detail by genome-wide array comparative genomic hybridization in Ring-containing tumor samples from soft tissue (n=15) and bone (n=6), using tiling resolution microarrays, encompassing 32 433 bacterial artificial chromosome clones. The DNA copy number profiles revealed multiple amplification targets, in many cases highly discontinuous, leading to delineation of large numbers of very small amplicons. A total number of 356 (median size: 0.64 Mb) amplicons were seen in the soft tissue tumors and 90 (median size: 1.19 Mb) in the bone tumors. Notably, more than 40% of all amplicons in both soft tissue and bone tumors were mapped to chromosome 12, and at least one of the previously reported recurrent amplifications in 12q13.3–14.1 and 12q15.1, including SAS and CDK4, and MDM2, respectively, were present in 85% of the soft tissue tumors and in all of the bone tumors. Although chromosome 12 was the only chromosome displaying recurrent amplification in the bone tumors, the soft tissue tumors frequently showed recurrent amplicons mapping to other Chromosomes, that is, 1p32, 1q23–24, 3p11–12, 6q24–25 and 20q11–12. Of particular interest, amplicons containing genes involved in the c-jun NH2-terminal kinase/mitogen-activated protein kinase pathway, that is, JUN in 1p32 and MAP3K7IP2 (TAB2) in 6q24–25, were found to be independently amplified in eight of 11 cases with 12q amplification, providing strong support for the notion that aberrant expression of this pathway is an important step in the dedifferentiation of liposarcomas.
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Ring Chromosomes and low grade gene amplification in an atypical lipomatous tumor with minimal nuclear atypia
International Journal of Oncology, 2003Co-Authors: Clelia Tiziana Storlazzi, Henryk A Domanski, Fredrik Mertens, Christopher D M Fletcher, Joop Wiegant, Nils MandahlAbstract: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. (Less)
Anders Rydholm - One of the best experts on this subject based on the ideXlab platform.
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deep seated ordinary and atypical lipomas histopathology cytogenetics clinical features and outcome in 215 tumours of the extremity and trunk wall
Journal of Bone and Joint Surgery-british Volume, 2008Co-Authors: V Billing, Henryk A Domanski, Fredrik Mertens, Anders RydholmAbstract:Deep-seated lipomas are often atypical histologically and are considered by some to have a high risk of recurrence after excision. We reviewed 215 deep-seated lipomas of the extremities and trunk wall with reference to histology, cytogenetics, clinical features and local recurrence. We classified tumours with atypical features and/or Ring Chromosomes as atypical lipomas. These were more common in men, larger than ordinary lipomas and more often located in the upper leg. The annual incidence was estimated as ten per million inhabitants and the ratio of atypical to ordinary lipomas was 1:3. In total, six tumours (3%), recurred locally after a median of eight years (1 to 16); of these, four were classified as atypical. The low recurrence rate of deep-seated lipomas of the extremity or trunk wall, irrespective of histological subtype, implies that if surgery is indicated, the tumour may be shelled out, that atypical lipomas in these locations do not deserve the designation well-differentiated liposarcoma, and that routine review after surgery is not required.
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the chimeric fus creb3l2 gene is specific for low grade fibromyxoid sarcoma
Genes Chromosomes and Cancer, 2004Co-Authors: Ioannis Panagopoulos, Clelia Tiziana Storlazzi, Henryk A Domanski, Christopher D M Fletcher, Otte Brosjo, Jonathan A Fletcher, Antonio G Nascimento, Johan Wejde, Anders RydholmAbstract:Low-grade fibromyxoid sarcoma (LGFMS) is a variant of fibrosarcoma that was recognized as a distinct tumor entity only quite recently. We previously described a translocation, t(7;16)(q33;p11), that resulted in a fusion of the FUS and CREB3L2 (also known as BBF2H7) genes in two soft tissue tumors that fulfilled morphologic criteria for LGFMS. To delineate the spectrum of tumors that may harbor the FUS/CREB3L2 gene, we selected 45 low-grade spindle cell sarcomas for reverse transcriptase polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH) analyses; none of these tumors had originally been diagnosed as LGFMS. Furthermore, also included were two benign soft tissue tumors and nine high-grade sarcomas with supernumerary Ring Chromosomes or 7q3 rearrangement and three tumors diagnosed as LGFMS prior to the genetic analysis. Of the 59 tumors analyzed, 12 were FUS/CREB3L2-positive, all of which were diagnosed at histopathologic re-examination as being LGFMS, of both the classical subtype and the subtype with giant collagen rosettes. The breakpoints in the fusion transcripts were always in exons 6 or 7 of FUS and exon 5 of CREB3L2. The results indicated that FUS/CREB3L2 is specifically associated with LGFMS and that RT-PCR or FISH analysis may be useful for the differential diagnosis.
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cytogenetic analysis of 46 pleomorphic soft tissue sarcomas and correlation with morphologic and clinical features a report of the champ study group
Genes Chromosomes and Cancer, 1998Co-Authors: Fredrik Mertens, Nils Mandahl, Christopher D M Fletcher, Felix Mitelman, Anders Rydholm, Ivo De Wever, Juan Rosai, Raf Sciot, Giovanni Tallini, Herman Van Den BergheAbstract:With the aim of identifying objective cytogenetic-morphologic correlations, we evaluated 46 pleomorphic soft tissue sarcomas (mainly diagnosed originally as malignant fibrous histiocytomas) with clonal chromosome aberrations both cytogenetically and morphologically as part of an international collaborative study. By detailed histopathologic examination, most cases could be categorized into specific tumor types. Eight sarcomas were diagnosed as lipogenic (4 pleomorphic, 1 combined pleomorphic and myxoid/round cell, and 3 dedifferentiated liposarcomas), 19 as myogenic [11 leiomyosarcomas, 1 rhabdomyosarcoma, 4 myosarcomas not otherwise specified (NOS), and 3 probable myosarcomas NOS], 8 as myxofibrosarcomas, 1 as a malignant peripheral nerve sheath tumor, 1 as malignant mesenchymoma, 1 as extraskeletal osteosarcoma, 1 as sarcoma resembling proliferative fasciitis, and 7 as pleomorphic sarcomas NOS. In a three-grade system, 10 tumors were grade 2 and 36 were grade 3. The majority had highly complex karyotypes. A total of 24 recurrent abnormalities (defined by their presence in at least five cases) were detected: Ring Chromosomes, homogeneously staining regions (hsr) and/or double minute Chromosomes (dmin), and structural rearrangement of 22 different chromosome bands or regions. The frequency and distribution of the recurrent karyotypic features were uneven. Grade 3 tumors displayed, on average, more aberrations per case than did grade 2 tumors. Nine of the selected abnormalities, including hsr/dmin and rearrangements of 19p13 and 19q13, were found only among the high-grade tumors. When the tumors were subdivided according to lineage of differentiation, the highest frequency of aberrations was seen in pleomorphic sarcomas NOS, followed by myxofibrosarcomas, myogenic sarcomas, and lipogenic sarcomas. None of the selected rearrangements was, however, specific for any of these subgroups. The sole consistent cytogenetic-morphologic association was that all three dedifferentiated liposarcomas had multiple abnormal clones, at least one of which contained supernumerary Ring Chromosomes. Due mainly to karyotype complexity, it therefore seems unlikely that cytogenetic analysis can assist in the differential diagnostic subclassification of pleomorphic sarcomas, nor was there any clear-cut indication that the karyotypic picture could be used to predict clinical outcome. Although the mean number of recurrent chromosome aberrations was almost twice as high in sarcomas that gave rise to metastases as among those that did not, no particular aberration was restricted to either of the two subgroups. Genes Chromosomes Cancer 22:16–25, 1998. © 1998 Wiley-Liss, Inc.
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19p marker chromosome correlates with relapse in malignant fibrous histiocytoma
Genes Chromosomes and Cancer, 1996Co-Authors: Peter F M Choong, Fredrik Mertens, Nils Mandahl, Helena Willen, Felix Mitelman, Andris Kreicbergs, Thor Alvegard, Anders RydholmAbstract:: In this study, we examined the relationship of 19p13 aberrations, usually leading to addition of unknown material (19p+), and Ring Chromosomes to clinical outcome in patients with malignant fibrous histiocytoma (MFH). Analysis of 69 MFHs revealed 19 tumors with 19p+ and 24 tumors with Ring Chromosomes. After a median follow-up period of 36 months, 24 patients developed metastases, and 27 patients developed local recurrences. Ten patients had both local recurrences and metastases. Local recurrence was more common in association with 19p+ than without. Metastasis was more common with 19p+ tumors in high-risk patients (tumor size > 5 cm and grade III-IV; n = 48) than those without 19p+. There was a trend suggesting fewer relapses after tumors with Ring Chromosomes. 19p+ may be an independent marker of unfavorable outcome in MFH.
Florence Pedeutour - One of the best experts on this subject based on the ideXlab platform.
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Complex t(5;8) involving the CSPG2 and PTK2B genes in a case of dermatofibrosarcoma protuberans without the COL1A1-PDGFB fusion.
Archiv für pathologische Anatomie und Physiologie und für klinische Medicin, 2008Co-Authors: Laurence Bianchini, Jean Michel Coindre, Mariepierre Simon, Georges Maire, Bernard Guillot, Jean-marie Joujoux, Philippe Follana, Florence PedeutourAbstract:Dermatofibrosarcoma protuberans (DFSP) is a rare, dermal neoplasm of intermediate malignancy. It is made of spindle-shaped tumor cells in a storiform pattern positive for CD34. Cytogenetically, DFSP cells are characterized by either supernumerary Ring Chromosomes composed of sequences derived from Chromosomes 17 and 22 or more rarely of translocations t(17;22). These chromosomal rearrangements lead to the formation of a specific chimeric gene fusing COL1A1 to PDGFB. So far, the COL1A1-PDGFB fusion gene remains the sole fusion gene identified in DFSP. However, some observations suggest that genes, other than COL1A1 and PDGFB, might be involved in some DFSP cases. We report in this paper a DFSP case presenting as a unique chromosomal abnormality a complex translocation between Chromosomes 5 and 8. This is the first report of a DFSP case where the lack of Chromosomes 17 and 22 rearrangement and the absence of COL1A1-PDGFB fusion gene have been demonstrated. Using fluorescence in situ hybridization analysis, we showed that the CSPG2 gene at 5q14.3 and the PTK2B gene at 8p21.2 were disrupted by this rearrangement. Although rare, the existence of cases of DFSP negative for the COL1A1-PDGFB fusion has to be taken in consideration when performing molecular diagnosis for a tumor suspected to be a DFSP.
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dedifferentiated liposarcoma of the pleura mimicking a malignant solitary fibrous tumor and associated with dedifferentiated liposarcoma of the mediastinum usefulness of cytogenetic and molecular genetic analyses
Cancer Genetics and Cytogenetics, 2007Co-Authors: Maxime Benchetritt, Florence Pedeutour, Veronique Hofman, Nicolas Venissac, Caroline Brennetot, Bernard Padovani, Alain Aurias, Antoine Italiano, P HofmanAbstract:Dedifferentiated liposarcoma of the pleura is an extremely rare malignancy mimicking a variety of tumors, such as other sarcomas, mesothelioma, and malignant solitary fibrous tumor of the pleura. Liposarcoma of the pleura can be combined with mediastinal involvement, and in most cases it may be impossible to be certain where the primary tumor originated. In this report, we describe a very rare occurence of a dedifferentiated liposarcoma of the pleura in a 76-year-old woman associated with a distinct second dedifferentiated liposarcoma of the mediastinum. Histologically, the pleural tumor demonstrated spindle cells arranged in a fascicular pattern, whereas the mediastinal tumor was mostly adipocytic with small areas of spindle cells. Vimentin and protein S100 were focally expressed by the tumor cells. The differential diagnosis of the pleural mass included malignant solitary fibrous tumor. Cytogenetic analysis showed supernumerary Ring Chromosomes in the pleural tumor, as well as strong amplification of MDM2 and CDK4 genes in both tumors. Array comparative genomic hybridization showed amplifications of chromosome arms 6q, 12q, and 15q, shared by both tumors and strongly pointing to a common origin.
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deregulation of the platelet derived growth factor b chain gene via fusion with collagen gene col1a1 in dermatofibrosarcoma protuberans and giant cell fibroblastoma
Nature Genetics, 1997Co-Authors: Mariepierre Simon, Florence Pedeutour, Nils Mandahl, Fabiola Minoletti, M J Terrierlacombe, Jean Michel Coindre, Nicolas Sirvent, J Grosgeorge, Randall D Craver, Nikolaus BlinAbstract:Dermatofibrosarcoma protuberans (DP), an infiltrative skin tumour of intermediate malignancy1, presents specific features such as reciprocal translocations t(17;22)(q22;q13) and supernumerary Ring Chromosomes derived from the t(17;22)2,3. In this report, the breakpoints from translocations and Rings in DP and its juvenile form, giant cell fibroblastoma (GCF)4,5, were characterised on the genomic and RNA level. These rearrangements fuse the platelet-derived growth factor B-chain (PDGFB, c-sis proto-oncogene) and the collagen type I α1 (COL1A1) genes. PDGFB has transforming activity and is a potent mitogen for a number of cell types, but its role in oncogenic processes is not fully understood6,7. COL1A1 is a major constituent of the connective tissue matrix8. Neither PDGFB nor COL1A1 have so far been implicated in any tumour translocations. These gene fusions delete exon 1 of PDGFB, and release this growth factor from its normal regulation.
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translocation t 17 22 q22 q13 in dermatofibrosarcoma protuberans a new tumor associated chromosome rearrangement
Cytogenetic and Genome Research, 1996Co-Authors: Florence Pedeutour, G. Barceló, M P Simon, Fabiola Minoletti, M J Terrierlacombe, P Combemale, Gabriella Sozzi, N Ayraud, Claude TurccarelAbstract:A translocation, t(17;22)(q22;ql 3), was identified in two cases of dermatofibrosarcoma protuberans (DP). They bRing to four the number of DP cases characterized by an identical t(17;22)(q22;q13), which can be considered as a new tumor-associated chromosome rearrangement. To date, this translocation has been found only in DP and its juvenile form, giant-cell fibroblastoma. This finding has two major consequences. First, it casts light on the development and significance in DP of Ring Chromosomes which consistently harbor sequences derived from Chromosomes 17 and 22. Second, the identification of this new chromosome marker, and eventually of the underlying molecular rearrangement, should help to classify DP, a soft-tissue tumor of still uncertain cell origin. In addition, it could be used to differentiate DP from truly benign or malignant entities, in order that this tumor of intermediate malignancy could be adequately managed.
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Ring 22 Chromosomes in dermatofibrosarcoma protuberans are low level amplifiers of chromosome 17 and 22 sequences
Cancer Research, 1995Co-Authors: Florence Pedeutour, Fabiola Minoletti, Gabriella Sozzi, M A Pierotti, Frederick Hecht, Mariepierre Simon, Claude TurccarelAbstract:Abstract Ring Chromosomes have been found with some regularity as solid tumors have come increasingly under cytogenetic study. The full genetic content and significance of these Rings remain unclear. Dermatofibrosarcoma protuberans, a tumor of the deep dermis, consistently has supernumerary Ring Chromosomes, sometimes as the sole detectable cytogenetic change. Using a modified method for comparative genomic hybridization and fluorescent in situ hybridization with a panel of various probes, we found that these Ring Chromosomes consistently contain the chromosome 22 centromere along with interstitial sequences from Chromosomes 17 and 22, specifically from regions 17q23–24 and 22q11–12. The Ring Chromosomes in dermatofibrosarcoma protuberans are vehicles for a particular pattern of relatively low-level genomic amplification of selected sequences.
Martin Poot - One of the best experts on this subject based on the ideXlab platform.
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Gain of FAM123B and ARHGEF9 in an Obese Man with Intellectual Disability, Congenital Heart Defects and Multiple Supernumerary Ring Chromosomes
Molecular syndromology, 2012Co-Authors: Ron Hochstenbach, M.e. Van Gijn, P.j. Krijtenburg, R. Raemakers, R. Van ’t Slot, Ivo Renkens, Marc J. Eleveld, J.j. Van Der Smagt, Martin PootAbstract:In a 24-year-old man with mild intellectual disability, congenital heart defects and obesity, we identified up to 4 small supernumerary marker Chromosomes (sSMCs) in blood metaphases. The Ring-shaped sSMCs were derived from Chromosomes 11, 12 and X as well as a fourth, unidentified chromosome. In interphase nuclei of epithelial cells from the urinary tract and buccal mucosa, the presence of the r(11), r(12) and r(X) was confirmed by FISH. Using Illumina Infinium 317K SNP-arrays, we detected 3 copies of the pericentromeric regions of Chromosomes 11, 12 and X. The r(X) was present in 84–89% of cells in the various tissues examined, lacks the XIST gene, but contains FAM123B, a potential dosage-sensitive candidate gene for congenital cardiac abnormalities, and ARHGEF9, a candidate gene for intellectual disability. ARHGEF9 encodes collybistin (CB), which is required for localization of the inhibitory receptor-anchoRing protein gephyrin and for formation and maintenance of postsynaptic GABAA and glycine receptors. We propose that the 2-fold increase in dosage of ARHGEF9 disturbs the stoichiometry of CB with its interacting proteins at inhibitory postsynapses. SNP alleles and short tandem repeat markers on the r(11) and r(X) were compatible with a maternal origin of both sSMCs through a meiosis II error. The sSMCs may have resulted from predivision chromatid nondisjunction, leading to anaphase lagging, followed by incomplete degradation of the supernumerary Chromosomes.
