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| 2. |
- Bartuma, Hammurabi, et al.
(author)
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Cytogenetic and molecular cytogenetic findings in lipoblastoma.
- 2008
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In: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 183:1, s. 60-63
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Journal article (peer-reviewed)abstract
- Lipoblastoma is a rare benign tumor that arises from embryonic adipose tissue and usually occurs in young children. Here, we present a review of available cytogenetic data and the karyotypes of 10 new cases of lipoblastoma, of which 7 could be studied further by fluorescence in situ hybridization (FISH) with regard to the involvement of the PLAG1 gene. All seven tumors with clonal aberrations harbored breakpoints in 8q11 approximately q13, in agreement with literature data. Including previously published cases, 33/40 (82%) lipoblastomas had rearrangement of the 8q11 approximately q13 region. These rearrangements target the PLAG1 gene, which becomes upregulated through promoter swapping. FISH revealed that five of seven cases in our series had a rearrangement of the PLAG1 gene. Occasionally, there can be difficulties in distinguishing a lipoblastoma from a conventional lipoma or a myxoid liposarcoma. As 8q11 approximately q13 rearrangements have been reported in only 3% of conventional lipomas and never in myxoid liposarcoma, cytogenetic analysis or FISH for the PLAG1 gene can provide useful differential diagnostic information.
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| 3. |
- Bartuma, Hammurabi, et al.
(author)
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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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In: Cancer Genetics and Cytogenetics. - : Elsevier BV. - 0165-4608. ; 199:2, s. 143-146
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Journal article (peer-reviewed)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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| 4. |
- Gebre-Medhin, Samuel, et al.
(author)
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Recurrent Rearrangement of the PHF1 Gene in Ossifying Fibromyxoid Tumors.
- 2012
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In: American Journal of Pathology. - : Elsevier BV. - 1525-2191 .- 0002-9440. ; 181:3, s. 1069-1077
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Journal article (peer-reviewed)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.
(author)
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Heterogeneous genetic profiles in soft tissue myoepitheliomas
- 2008
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In: Modern Pathology. - : Elsevier BV. - 1530-0285 .- 0893-3952. ; 21:11, s. 1311-1319
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Journal article (peer-reviewed)abstract
- Myoepithelioma, mixed tumor and parachordoma are uncommon soft tissue tumors thought to represent morphological variants of a single tumor type. The genetic basis of these neoplasms is poorly understood. However, they morphologically resemble mixed tumor of the salivary glands (also known as pleomorphic adenoma), a tumor characterized by deregulated expression of PLAG1 or HMGA2. To evaluate a possible genetic relationship between these soft tissue and salivary gland tumors, PLAG1 expression levels and the genomic status of PLAG1 and HMGA2 were investigated in five soft tissue myoepitheliomas and one pleomorphic adenoma. In addition, all tumors were cytogenetically investigated and whole genome DNA copy number imbalances were studied in five of them. The genetic profiles were heterogeneous and the only aberration common to all soft tissue myoepitheliomas was a minimally deleted region of 3.55 Mb in chromosome band 19p13. Recurrent deletion of CDKN2A suggests that inactivation of this tumor suppressor gene is pathogenetically important in a subset. Furthermore, PLAG1 rearrangement was found in a soft tissue tumor from a patient previously treated for a salivary pleomorphic adenoma, indicating either metastasis of the salivary gland lesion or that some soft tissue tumors develop through the same mechanisms as their salivary gland counterparts.
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| 6. |
- Hofvander, Jakob, et al.
(author)
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RNA sequencing of sarcomas with simple karyotypes: identification and enrichment of fusion transcripts.
- 2015
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In: Laboratory Investigation. - : Elsevier BV. - 1530-0307 .- 0023-6837. ; 95:6, s. 603-609
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Journal article (peer-reviewed)abstract
- Gene fusions are neoplasia-associated mutations arising from structural chromosomal rearrangements. They have a strong impact on tumor development and constitute important diagnostic markers. Malignant soft tissue tumors (sarcomas) constitute a heterogeneous group of neoplasms with >50 distinct subtypes, each of which is rare. In addition, there is considerable morphologic overlap between sarcomas and benign lesions. Several subtypes display distinct gene fusions, serving as excellent biomarkers. The development of methods for deep sequencing of the complete transcriptome (RNA-Seq) has substantially improved the possibilities for detecting gene fusions. With the aim of identifying new gene fusions of biological and clinical relevance, eight sarcomas with simple karyotypes, ie, only one or a few structural rearrangements, were subjected to massively parallel paired-end sequencing of mRNA. Three different algorithms were used to identify fusion transcripts from RNA-Seq data. Three novel (KIAA2026-NUDT11, CCBL1-ARL1, and AFF3-PHF1) and two previously known fusions (FUS-CREB3L2 and HAS2-PLAG1) were found and could be verified by other methods. These findings show that RNA-Seq is a powerful tool for detecting gene fusions in sarcomas but also suggest that it is advisable to use more than one algorithm to analyze the output data as only two of the confirmed fusions were reported by more than one of the gene fusion detection software programs. For all of the confirmed gene fusions, at least one of the genes mapped to a chromosome band implicated by the karyotype, suggesting that sarcomas with simple karyotypes constitute an excellent resource for identifying novel gene fusions.Laboratory Investigation advance online publication, 13 April 2015; doi:10.1038/labinvest.2015.50.
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| 7. |
- Jin, Yuesheng, et al.
(author)
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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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In: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257. ; 51:5, s. 510-520
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Journal article (peer-reviewed)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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| 8. |
- Mohajeri, Arezoo, et al.
(author)
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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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In: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 52:10, s. 873-886
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Journal article (peer-reviewed)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.
(author)
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Fusions involving protein kinase C and membrane-associated proteins in benign fibrous histiocytoma.
- 2014
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In: International Journal of Biochemistry & Cell Biology. - : Elsevier BV. - 1878-5875 .- 1357-2725. ; 53:Apr 8, s. 475-481
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Journal article (peer-reviewed)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. |
- Storlazzi, CT, et al.
(author)
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Biallelic somatic inactivation of the NF1 gene through chromosomal translocations in a sporadic neurofibroma
- 2005
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In: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 117:6, s. 1055-1057
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Journal article (peer-reviewed)abstract
- Neurofibroma is a benign tumor originating from Schwann cells in peripheral nerve sheaths and may occur as a sporadic tumor or as part of the dominantly inherited tumor syndrome NF1. NF1 is caused by constitutional mutations in the NF1 gene, located in chromosome band 17q11 Whereas the involvement of the NF1 gene in neurofibroma development in NF1 patients has been fairly well characterized, the significance of inactivation of this gene in sporadic neurofibromas remains less well investigated. Inactivation of both copies of NF1 has been described in a few neurofibromas from NF1 patients, and LOH at the same locus has been reported in additional cases. In the present study, we report the cytogenetic and molecular cytogenetic findings in a sporadic neurofibroma that at G-banding analysis showed a translocation between one chromosome 2 and the long arms of both copies of chromosome 17. FISH analysis using a set of 3 BAC clones covering the entire coding region of NF1 revealed the complete loss of one allele and the deletion of the 5' portion of the second allele as a result of 2 translocation events. To the best of our knowledge, this represents the first demonstration of a somatic biallelic inactivation of the NF1 gene in neurofibroma, providing further evidence for the importance of NF1 inactivation also in sporadic neurofibromas.
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