Browsing by Author "Nord, Karolin H."

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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
    (Genes, Chromosomes and Cancer, 2013) Mohajeri, Arezoo; Tayebwa, Johnbosco; Collin, Anna; Nilsson, Jenny; Magnusson, Linda; Vult von Steyern, Fredrik; Brosj, Otte; Domanski, Henryk A.; Larsson, Olle; Sciot, Raf; Debiec-Rychter, Maria; Hornick, Jason L.; Mandahl, Nils; Nord, Karolin H.; Mertens, Fredrik
    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.
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    Fusions involving protein kinase C and membrane-associated proteinsin benign fibrous histiocytoma
    (he International Journal of Biochemistry & Cell Biology,, 2014) Płaszczyca, Anna; Nilsson, Jenny; Magnusson, Linda; Brosjö, Otte; Larsson, Olle; Vult von Steyernd, Fredrik; Domanski, Henryk A.; Lilljebjörn, Henrik; Fioretos, Thoas; Tayebwa, Johnbosco; Mandahl, Nils; Nord, Karolin H.; Mertens, Fredrik
    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 itis a true neoplasm. Chromosome banding, fluorescence in situ hybridization, single nucleotide polymor-phism arrays, RNA sequencing, RT-PCR and quantitative real-time PCR were used to search for re current 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 kinaseC (PKC) isoforms PRKCB and PRKCD. PKCs are serine–threonine kinases that through their many phos-phorylation 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-PRKCDgene 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 atrue 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.
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    GRM1 is upregulated through gene fusion and promoter swapping in chondromyxoid fibroma
    (Nature genetics, 2014) Nord, Karolin H.; Lilljebjörn, Henrik; Vezzi, Francesco; Nilsson, Jenny; Magnusson, Linda; Tayebwa, Johnbosco; Jong, Danielle de; Bovée, Judith V. M. G.; Hogendoorn, Pancras C. W.; Szuhai, Karoly
    Glutamate receptors are well-known actors in the central and peripheral nervous systems, and altered glutamate signaling is implicated in several neurological and psychiatric disorders. It is increasingly recognized that such receptors may also have a role in tumor growth. Here we provide direct evidence of aberrant glutamate signaling in the development of a locally aggressive bone tumor, chondromyxoid fibroma (CMF). We subjected a series of CMFs to whole-genome mate-pair sequencing and RNA sequencing and found that the glutamate receptor gene GRM1 recombines with several partner genes through promoter swapping and gene fusion events. The GRM1 coding region remains intact, and 18 of 20 CMFs (90%) showed a more than 100-fold and up to 1,400-fold increase in GRM1 expression levels compared to control tissues. Our findings unequivocally demonstrate that direct targeting of GRM1 is a necessary and highly specific driver event for CMF development.
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    A novel SERPINE1–FOSB fusion gene results in transcriptional up-regulation of FOSB in pseudomyogenic haemangioendothelioma
    (The Journal of Pathology, 2014) Walther, Charles; Tayebwa, Johnbosco; Lilljebjorn, Henrik; Magnusson, Linda; Nilsson, Jenny; Vult von Steyern, Fredrik; Øra, Ingrid; Domanski, Henryk A.; Fioretos, Thoas; Nord, Karolin H.; Fletcher, Christopher D. M.
    Pseudomyogenic haemangioendothelioma (PHE) is an intermediate malignant vascular soft tissue tumour primarily affecting children and young adults. The molecular basis of this neoplasm is unknown. We here used chromosome banding analysis, fluorescence in situ hybridization (FISH), mRNA sequencing, RT–PCR and quantitative realtime PCR on a series of morphologically well-characterized PHEs to show that a balanced translocation, t(7;19)(q22;q13), detected as the sole cytogenetic aberration in two cases, results in fusion of the SERPINE1 and FOSB genes. This translocation has not been observed in any other bone or soft tissue tumour. Interphase FISH on sections from eight additional PHEs identified the same SERPINE1–FOSB fusion in all cases. The role of SERPINE1, which is highly expressed in vascular cells, in this gene fusion is probably to provide a strong promoter for FOSB, which was found to be expressed at higher levels in PHEs than in other soft tissue tumours. FOSB encodes a transcription factor belonging to the FOS family of proteins, which, together with members of the JUN family of transcription factors, are major components of the activating protein 1 (AP-1) complex. Further studies are needed to understand the cellular impact of the aberrant expression of the FOSB gene, but as the t(7;19) resulting in the SERPINE1–FOSB fusion seems to be pathognomonic for PHE, FISH or RT–PCR could be useful for differential diagnostic purposes.
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    Recurrent EWSR1-CREB3L1 Gene Fusions in Sclerosing Epithelioid Fibrosarcoma
    (The American journal of surgical pathology, 2014) Arbajian, Elsa; Puls, Florian; Magnusson, Linda; Thway, Khin; Fisher, Cyril; Sumathi, Vaiyapuri P.; Tayebwa, Johnbosco; Nord, Karolin H.; Kindblom, Lars-Gunnar; Mertens, Fredrik
    Sclerosing epithelioid fibrosarcoma (SEF) and lowgrade fibromyxoid sarcoma (LGFMS) are 2 distinct types of sarcoma, with a subset of cases showing overlapping morphologic and immunohistochemical features. LGFMS is characterized by expression of the MUC4 protein, and about 90% of cases display a distinctive FUS-CREB3L2 gene fusion. In addition, SEF is often MUC4 positive, but is genetically less well studied. Fluorescence in situ hybridization (FISH) studies have shown involvement of the FUS gene in the majority of so-called hybrid LGFMS/SEF and in 10% to 25% of sarcomas with pure SEF morphology. In this study, we investigated a series of 10 primary tumors showing pure SEF morphology, 4 cases of LGFMS that at local or distant relapse showed predominant SEF morphology, and 1 primary hybrid LGFMS/SEF. All but 1 case showed diffuse expression for MUC4. Using FISH, reverse transcription polymerase chain reaction, and/or mRNA sequencing in selected cases, we found recurrent EWSR1-CREB3L1 fusion transcripts by reverse transcription polymerase chain reaction in 3/10 pure SEF cases and splits and deletions of the EWSR1 and/or CREB3L1 genes by FISH in 6 additional cases. All 5 cases of LGFMS with progression to SEF morphology or hybrid features had FUS-CREB3L2 fusion transcripts. Our results indicate that EWSR1 and CREB3L1 rearrangements are predominant over FUS and CREB3L2 rearrangements in pure SEF, highlighting that SEF and LGFMS are different tumor types, with different impacts on patient outcome.