| 1. |
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| 2. |
- Bartuma, Hammurabi, et al.
(författare)
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Fusion of the FUS and CREB3L2 genes in a supernumerary ring chromosome in low-grade fibromyxoid sarcoma.
- 2010
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Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 199:2, s. 143-146
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 3. |
- Brune, Jan Claas, et al.
(författare)
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Mesenchymal stromal cells from primary osteosarcoma are non-malignant and strikingly similar to their bone marrow counterparts.
- 2011
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 129, s. 319-330
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Tidskriftsartikel (refereegranskat)abstract
- Mesenchymal stromal cells (MSC) are multipotent cells that can be isolated from a number of human tissues. In cancer, MSC have been implicated with tumor growth, invasion, metastasis, drug resistance and were even suggested as possible tumor-initiating cells in osteosarcoma (OS). However, MSC from OS and their possible tumor origin have not yet been thoroughly investigated. Therefore, primary OS mesenchymal progenitors and OS-derived MSC were studied. OS samples contained very high frequencies of mesenchymal progenitor cells as measured by the CFU-F assay (median: 1,117 colonies per 10(5) cells, range: 133 - 3,000, n=6). This is considerably higher compared to other human tissues such as normal bone marrow (1.3 ± 0.2 colonies per 10(5) cells, n=8). OS-derived MSC (OS-MSC) showed normal MSC morphology and expressed the typical MSC surface marker profile (CD105/CD73/CD90/CD44/HLA-classI/CD166 positive, CD45/CD34/CD14/CD19/HLA-DR/CD31 negative). Furthermore, all OS-MSC samples could be differentiated into the osteogenic lineage, and all but one sample into adipocytes and chondrocytes. Genetic analysis of OS-MSC as well as OS-derived spheres showed no tumor-related chromosomal aberrations. OS-MSC expression of markers related to tumor-associated fibroblasts (fibroblast surface protein, alpha-smooth muscle actin, vimentin) was comparable to bone marrow MSC and OS-MSC growth was considerably affected by tyrosine kinase inhibitors. Taken together, our results demonstrate that normal, non-malignant mesenchymal stroma cells are isolated from OS when MSC culture techniques are applied. OS-MSC represent a major constituent of the tumor microenvironment, and they share many properties with bone marrow-derived MSC. © 2010 UICC.
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| 4. |
- Gebre-Medhin, Samuel, et al.
(författare)
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Recurrent Rearrangement of the PHF1 Gene in Ossifying Fibromyxoid Tumors.
- 2012
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Ingår i: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 181:3, s. 1069-1077
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Tidskriftsartikel (refereegranskat)abstract
- Ossifying fibromyxoid tumor (OFMT) is a soft tissue tumor of unknown lineage. Although most cases are histologically and clinically benign, some show malignant morphological features and local recurrences are not uncommon; a few may even metastasize. In the present study, cytogenetic analysis identified different structural rearrangements of chromosome band 6p21 in tumor cells from three cases of OFMT, including one with typical, one with atypical, and one with malignant morphological features. Mapping of the 6p21 breakpoint by fluorescence in situ hybridization (FISH) indicated that the PHF1 gene was rearranged in all three cases. Further FISH, 5'-rapid amplification of cDNA ends, and RT-PCR analyses disclosed an EP400/PHF1 fusion transcript in one of the cases. Interphase FISH on tumor sections from 13 additional cases of OFMT showed rearrangement of the PHF1 locus in four of four typical, two of three atypical, and one of six malignant lesions. Thus, the PHF1 gene, previously shown to be the 3'-partner of fusion genes in endometrial stromal tumors, is also recurrently involved in the pathogenesis of OFMTs, irrespective of whether they are diagnosed as typical, atypical, or malignant lesions. The PHF1 protein interacts with the polycomb-repressive complex 2 (PRC2), which, in turn, regulates the expression of a variety of developmental genes. Thus, the results indicate that deregulation of PRC2 target genes is crucial for OFMT development.
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| 5. |
- Hansén Nord, Karolin, et al.
(författare)
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Integrative Genome and Transcriptome Analyses Reveal Two Distinct Types of Ring Chromosome in Soft Tissue Sarcomas.
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:4, s. 878-888
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Jin, Yuesheng, et al.
(författare)
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Fusion of the AHRR and NCOA2 genes through a recurrent translocation t(5;8)(p15;q13) in soft tissue angiofibroma results in upregulation of aryl hydrocarbon receptor target genes.
- 2012
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 51:5, s. 510-520
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Tidskriftsartikel (refereegranskat)abstract
- Soft tissue angiofibroma is a recently delineated tumor type of unknown cellular origin. Cytogenetic analysis of four cases showed that they shared a t(5;8)(p15;q13). In three of them it was the sole change, underlining its pathogenetic significance. FISH mapping suggested the involvement of the aryl hydrocarbon receptor repressor (AHRR) and nuclear receptor coactivator 2 (NCOA2) genes in 5p15 and 8q13, respectively. RT-PCR revealed in-frame AHRR/NCOA2 and NCOA2/AHHR transcripts in all four cases. Interphase FISH on paraffin-embedded tissue from 10 further cases without cytogenetic data showed that three were positive for fusion of AHRR and NCOA2. While AHRR has never been implicated in gene fusions before, NCOA2 is the 3'-partner in fusions with MYST3 and ETV6 in leukemias and with PAX3 and HEY1 in sarcomas. As in the previously described fusion proteins, NCOA2 contributes with its two activation domains to the AHRR/NCOA2 chimera, substituting for the repressor domain of AHRR. Because the amino terminal part of the transcription factor AHRR, responsible for the recognition of xenobiotic response elements in target genes and for heterodimerization, shows extensive homology with the aryl hydrocarbon receptor (AHR), the fusion is predicted to upregulate the AHR/ARNT signaling pathway. Indeed, global gene expression analysis showed upregulation of CYP1A1 as well as other typical target genes of this pathway, such as those encoding toll-like receptors. Apart from providing a diagnostic marker for soft tissue angiofibroma, the results also suggest that this tumor constitutes an interesting model for evaluating the cellular effects of AHR signaling. © 2012 Wiley Periodicals, Inc.
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| 7. |
- Mertens, Fredrik, et al.
(författare)
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The MDM2 SNP309 G allele is not preferentially amplified in bone and soft tissue tumors.
- 2012
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Ingår i: Cancer Genetics. - : Elsevier BV. - 2210-7762. ; 205:9, s. 470-473
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Tidskriftsartikel (refereegranskat)abstract
- The transcriptional enhancer region in intron 1 of the proto-oncogene MDM2 contains a polymorphic site (SNP309) that may harbor a G or a T nucleotide. Previous studies have shown that the G allele confers a higher affinity for the Sp1 transcription factor, resulting in an increased transcriptional activity of MDM2. A constitutional G allele has also been associated with earlier onset of various cancer types, and studies of sarcomas have shown an enrichment of the G allele in tumors with MDM2 amplification, notably atypical lipomatous tumor (also known as well-differentiated liposarcoma). In the present study, we analyzed the SNP309 genotype in blood samples and tumor tissue from 57 patients with bone or soft tissue tumors showing amplification of MDM2. We did not observe any constitutional enrichment of the G allele. More importantly, there was no preferential amplification of the G allele in tumor tissue from TG heterozygotes. The expression levels of MDM2 messenger RNA were not higher in tumors with amplification of the G allele than in tumors with amplification of the T allele. Thus, we could not find any evidence for a selective advantage of the SNP309 G allele in bone and soft tissue tumors with MDM2 amplification.
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| 8. |
- Mohajeri, Arezoo, et al.
(författare)
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Comprehensive genetic analysis identifies a pathognomonic NAB2/STAT6 fusion gene, nonrandom secondary genomic imbalances, and a characteristic gene expression profile in solitary fibrous tumor.
- 2013
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 52:10, s. 873-886
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Tidskriftsartikel (refereegranskat)abstract
- Solitary fibrous tumor (SFT) is a mesenchymal neoplasm displaying variable morphologic and clinical features. To identify pathogenetically important genetic rearrangements, 44 SFTs were analyzed using a variety of techniques. Chromosome banding and fluorescence in situ hybridization (FISH) showed recurrent breakpoints in 12q13, clustering near the NAB2 and STAT6 genes, and single nucleotide polymorphism array analysis disclosed frequent deletions affecting STAT6. Quantitative real-time PCR revealed high expression levels of the 5'-end of NAB2 and the 3'-end of STAT6, which at deep sequencing of enriched DNA corresponded to NAB2/STAT6 fusions. Subsequent reverse-transcriptase PCR (RT-PCR) analysis identified a NAB2/STAT6 fusion in 37/41 cases, confirming that this fusion gene underlies the pathogenesis of SFT. The hypothesis that the NAB2/STAT6 fusions will result in altered properties of the transcriptional co-repressor NAB2 - a key regulator of the early growth response 1 (EGR1) transcription factor - was corroborated by global gene expression analysis; SFTs showed deregulated expression of EGR1 target genes, as well as of other, developmentally important genes. We also identified several nonrandom secondary changes, notably loss of material from 13q and 14q. As neither chromosome banding nor FISH analysis identify more than a minor fraction of the fusion-positive cases, and because multiple primer combinations are required to identify all possible fusion transcripts by RT-PCR, alternative diagnostic markers might instead be found among deregulated genes identified at global gene expression analysis. Indeed, using immunohistochemistry on tissue microarrays, the top up-regulated gene, GRIA2, was found to be differentially expressed also at the protein level. © 2013 Wiley Periodicals, Inc.
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| 9. |
- Płaszczyca, Anna, et al.
(författare)
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Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma.
- 2014
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Ingår i: International Journal of Biochemistry & Cell Biology. - : Elsevier BV. - 1878-5875 .- 1357-2725. ; 53:Apr 8, s. 475-481
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Tidskriftsartikel (refereegranskat)abstract
- Benign fibrous histiocytoma (BFH) is a mesenchymal tumor that most often occurs in the skin (so-called dermatofibroma), but may also appear in soft tissues (so-called deep BFH) and in the skeleton (so-called non-ossifying fibroma). The origin of BFH is unknown, and it has been questioned whether it is a true neoplasm. Chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism arrays, RNA sequencing, RT-PCR and quantitative real-time PCR were used to search for recurrent somatic mutations in a series of BFH. BFHs were found to harbor recurrent fusions of genes encoding membrane-associated proteins (podoplanin, CD63 and LAMTOR1) with genes encoding protein kinase C (PKC) isoforms PRKCB and PRKCD. PKCs are serine-threonine kinases that through their many phosphorylation targets are implicated in a variety of cellular processes, as well as tumor development. When inactive, the amino-terminal, regulatory domain of PKCs suppresses the activity of their catalytic domain. Upon activation, which requires several steps, they typically translocate to cell membranes, where they interact with different signaling pathways. The detected PDPN-PRKCB, CD63-PRKCD and LAMTOR1-PRKCD gene fusions are all predicted to result in chimeric proteins consisting of the membrane-binding part of PDPN, CD63 or LAMTOR1 and the entire catalytic domain of the PKC. This novel pathogenetic mechanism should result in constitutive kinase activity at an ectopic location. The results show that BFH indeed is a true neoplasm, and that distorted PKC activity is essential for tumorigenesis. The findings also provide means to differentiate BFH from other skin and soft tissue tumors. This article is part of a Directed Issue entitled: Rare cancers.
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| 10. |
- Trombetta, Domenico, et al.
(författare)
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Translocation t(7;19)(q22;q13)-a recurrent chromosome aberration in pseudomyogenic hemangioendothelioma?
- 2011
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Ingår i: Cancer Genetics. - : Elsevier BV. - 2210-7762. ; 204:4, s. 211-215
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Tidskriftsartikel (refereegranskat)abstract
- Pseudomyogenic hemangioendothelioma is a recently described morphologic entity among soft tissue tumors. It is more common in young individuals, shows a male predominance, is often multifocal and involves different tissue planes, and shows a high propensity for local recurrence. To our knowledge, no genetic characteristics of this tumor type have been presented before. Here, we describe the finding of a balanced t(7;19)(q22;q13) as the sole anomaly in three lesions from a 14-year-old girl. By means of fluorescence in situ hybridization, the breakpoints could be delineated, but reverse transcriptase-polymerase chain reaction for putative fusion genes did not reveal any fusion transcript. Interphase fluorescence in situ hybridization on sections from nine other pseudomyogenic hemangioendotheliomas indicated the presence of an unbalanced der(7)t(7;19) in one of them. Thus, the translocation between chromosomes 7 and 19 seems to be a recurrent phenomenon and is likely to be of pathogenetic significance in at least a subset of pseudomyogenic hemangioendotheliomas.
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