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| 3. |
- Hofvander, Jakob, et al.
(författare)
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Frequent low-level mutations of protein kinase D2 in angiolipoma
- 2017
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Ingår i: Journal of Pathology. - : WILEY. - 0022-3417 .- 1096-9896. ; 241:5, s. 578-582
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Tidskriftsartikel (refereegranskat)abstract
- Tumours displaying differentiation towards normal fat constitute the most common subgroup of soft tissue neoplasms. A series of such tumours was investigated by whole-exome sequencing followed by targeted ultra-deep sequencing. Eighty per cent of angiolipomas, but not any other tumour type, displayed mutations in the protein kinase D2 (PRKD2) gene, typically in the part encoding the catalytic domain. The absence of other aberrations at the chromosome or RNA level suggests that PRKD2 mutations are critical for angiolipoma development. Consistently, the mutated PRKD2 alleles were present at low (3-15%) frequencies, indicating that only a subset of the tumour cells is affected. Indeed, by sequencing mature fat cells and other cells separately, the former typically showed the highest mutation frequencies. Thus, we hypothesize that altered PRKD2 signalling in the adipocytic cells drives tumourigenesis and, in agreement with its pivotal role in angiogenesis, induces the vessel formation that is characteristic for angiolipoma. Copyright (c) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley amp; Sons, Ltd.
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| 4. |
- Mandahl, Nils, et al.
(författare)
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Scattered genomic amplification in dedifferentiated liposarcoma
- 2017
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Ingår i: Molecular Cytogenetics. - : Springer Science and Business Media LLC. - 1755-8166. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- Background: Atypical lipomatous tumor (ALT), well differentiated liposarcoma (WDLS) and dedifferentiated liposarcoma (DDLS) are cytogenetically characterized by near-diploid karyotypes with no or few other aberrations than supernumerary ring or giant marker chromosomes, although DDLS tend to have somewhat more complex rearrangements. In contrast, pleomorphic liposarcomas (PLS) have highly aberrant and heterogeneous karyotypes. The ring and giant marker chromosomes contain discontinuous amplicons, in particular including multiple copies of the target genes CDK4, HMGA2 and MDM2 from 12q, but often also sequences from other chromosomes. Results: The present study presents a DDLS with an atypical hypertriploid karyotype without any ring or giant marker chromosomes. SNP array analyses revealed amplification of almost the entire 5p and discontinuous amplicons of 12q including the classical target genes, in particular CDK4. In addition, amplicons from 1q, 3q, 7p, 9p, 11q and 20q, covering from 2 to 14 Mb, were present. FISH analyses showed that sequences from 5p and 12q were scattered, separately or together, over more than 10 chromosomes of varying size. At RNA sequencing, significantly elevated expression, compared to myxoid liposarcomas, was seen for TRIO and AMACR in 5p and of CDK4, HMGA2 and MDM2 in 12q. Conclusions: The observed pattern of scattered amplification does not show the characteristics of chromothripsis, but is novel and differs from the well known cytogenetic manifestations of amplification, i.e., double minutes, homogeneously staining regions and ring chromosomes. Possible explanations for this unusual distribution of amplified sequences might be the mechanism of alternative lengthening of telomeres that is frequently active in DDLS and events associated with telomere crisis.
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| 5. |
- Al-Ibraheemi, Alyaa, et al.
(författare)
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Aberrant receptor tyrosine kinase signaling in lipofibromatosis : a clinicopathological and molecular genetic study of 20 cases
- 2019
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Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 32:3, s. 423-434
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Tidskriftsartikel (refereegranskat)abstract
- Lipofibromatosis is a rare pediatric soft tissue tumor with predilection for the hands and feet. Previously considered to represent “infantile fibromatosis”, lipofibromatosis has distinctive morphological features, with mature adipose tissue, short fascicles of bland fibroblastic cells, and lipoblast-like cells. Very little is known about the genetic underpinnings of lipofibromatosis. Prompted by our finding of the FN1-EGF gene fusion, previously shown to be a characteristic feature of calcifying aponeurotic fibroma (CAF), in a morphologically typical case of lipofibromatosis that recurred showing features of CAF, we studied a cohort of 20 cases of lipofibromatosis for this and other genetic events. The cohort was composed of 14 males and 6 females (median age 3 years; range 1 month–14 years). All primary tumors showed classical lipofibromatosis morphology. Follow-up disclosed three local recurrences, two of which contained calcifying aponeurotic fibroma-like nodular calcifications in addition to areas of classic lipofibromatosis, and no metastases. By FISH and RNA sequencing, four cases were positive for FN1-EGF and one case each showed an EGR1-GRIA1, TPR-ROS1, SPARC-PDGFRB, FN1-TGFA, EGFR-BRAF, VCL-RET, or HBEGF-RBM27 fusion. FN1-EGF was the only recurrent fusion, suggesting that some cases of “lipofibromatosis” may represent calcifying aponeurotic fibroma lacking hallmark calcifications. Several of the genes involved in fusions (BRAF, EGFR, PDGFRB, RET, and ROS1) encode receptor tyrosine kinases (RTK), or ligands to the RTK EGFR (EGF, HBEGF, TGFA), suggesting a shared deregulation of the PI3K–AKT–mTOR pathway in a large subset of lipofibromatosis cases.
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- Arbajian, Elsa, et al.
(författare)
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A Benign Vascular Tumor With a New Fusion Gene: EWSR1-NFATC1 in Hemangioma of the Bone.
- 2013
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Ingår i: American Journal of Surgical Pathology. - 1532-0979. ; 37:4, s. 613-616
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Tidskriftsartikel (refereegranskat)abstract
- The EWSR1 gene in chromosome band 22q12 is a promiscuous fusion partner involved in a vast array of tumors characterized by gene fusions. In this study, we report the finding of a new fusion gene, EWSR1-NFATC1, in a hemangioma of the bone; genetic rearrangements have not previously been described in this tumor type. Chromosome banding analysis showed a t(18;22)(q23;q12) translocation as the sole change. Fluorescence in situ hybridization mapping suggested the involvement of each of the 2 partner genes, and reverse transcriptase polymerase chain reaction revealed an in-frame EWSR1-NFATC1 transcript. NFATC1 has not previously been shown to be involved in a fusion chimera. However, NFATC2, encoding another member of the same protein family, is known to be a fusion partner for EWSR1 in a subgroup of Ewing sarcoma. Thus, our findings further broaden the spectrum of neoplasms associated with EWSR1 fusion genes, add a new partner to the growing list of EWSR1 chimeras, and suggest that chromosomal rearrangements of pathogenetic, and possibly also diagnostic, significance can be present in benign vascular bone tumors.
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| 7. |
- Arbajian, Elsa, et al.
(författare)
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Deep sequencing of myxoinflammatory fibroblastic sarcoma
- 2020
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Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:5, s. 309-317
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Tidskriftsartikel (refereegranskat)abstract
- Myxoinflammatory fibroblastic sarcoma (MIFS) has recurrent genetic features in the form of a translocation t(1;10)(p22-31;q24-25), BRAF gene fusions, and/or an amplicon in 3p11-12 including the VGLL3 gene. The breakpoints on chromosomes 1 and 10 in the t(1;10) cluster in or near the TGFBR3 and OGA genes, respectively. We here used a combination of deep sequencing of the genome (WGS), captured sequences (Cap-seq), and transcriptome (RNA-seq) and genomic arrays to investigate the molecular outcome of the t(1;10) and the VGLL3 amplicon, as well as to assess the spectrum of other recurrent genomic features in MIFS. Apart from a ROBO1-BRAF chimera in a t(1;10)-negative MIFS-like tumor, no fusion gene was found at RNA-seq. This was in line with WGS and Cap-seq results, revealing variable breakpoints in chromosomes 1 and 10 and genomic breakpoints that should not yield functional fusion transcripts. The most common genomic rearrangements were breakpoints in or around the OGA, NPM3, and FGF8 genes in chromosome band 10q24, and loss of 1p11-p21 and 10q26-qter (all simultaneously present in 6/7 MIFS); a breakpoint in or near TGFBR3 in chromosome 1 was found in four of these tumors. Amplification and overexpression of VGLL3 was a consistent feature in MIFS and MIFS-like tumors with amplicons in 3p11-12. The significant molecular genetic outcome of the recurrent t(1;10) could be loss of genetic material from 1p and 10q. Other recurrent genomic imbalances in MIFS, such as homozygous loss of CDKN2A and 3p- and 13q-deletions, are shared with other sarcomas, suggesting overlapping pathogenetic pathways. This article is protected by copyright. All rights reserved.
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| 8. |
- Arbajian, Elsa, et al.
(författare)
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In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets
- 2017
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Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:23, s. 7426-7434
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Sclerosing epithelioid fibrosarcoma (SEF) is a highly aggressive soft tissue sarcoma closely related to low-grade fibromyxoid sarcoma (LGFMS). Some tumors display morphological characteristics of both SEF and LGFMS, so called hybrid SEF/LGFMS. Despite the overlap of gene fusion variants between these two tumor types, SEF is much more aggressive. The present study aimed to further characterize SEF and hybrid SEF/LGFMS genetically in order to better understand the role of the characteristic fusion genes and possible additional genetic alterations in tumorigenesis.EXPERIMENTAL DESIGN: We performed whole exome sequencing, single nucleotide polymorphism (SNP) array analysis, RNA-sequencing (RNA-seq), global gene expression analyses and/or IHC on a series of 13 SEFs and 6 hybrid SEF/LGFMS. We also expressed the FUS-CREB3L2 and EWSR1-CREB3L1 fusion genes conditionally in a fibroblast cell line; these cells were subsequently analyzed by RNA-seq and expression of the CD24 protein was assessed by FACS analysis.RESULTS: The SNP array analysis detected a large number of structural aberrations in SEF and SEF/LGFMS, many of which were recurrent, notably DMD microdeletions. RNA-seq identified FUS-CREM and PAX5-CREB3L1 as alternative fusion genes in one SEF each. CD24 was strongly upregulated, presumably a direct target of the fusion proteins. This was further confirmed by the gene expression analysis and FACS analysis on Tet-On 3G cells expressing EWSR1-CREB3L1.CONCLUSIONS: While gene fusions are the primary tumorigenic events in both SEF and LGFMS, additional genomic changes explain the differences in aggressiveness and clinical outcome between the two types. CD24 and DMD constitute potential therapeutic targets.
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| 9. |
- Arbajian, Elsa, et al.
(författare)
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Recurrent EWSR1-CREB3L1 Gene Fusions in Sclerosing Epithelioid Fibrosarcoma.
- 2014
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Ingår i: American Journal of Surgical Pathology. - 1532-0979. ; 38:6, s. 801-808
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Tidskriftsartikel (refereegranskat)abstract
- Sclerosing epithelioid fibrosarcoma (SEF) and low-grade 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.
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| 10. |
- Köster, Jan, et al.
(författare)
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Genomic and transcriptomic features of dermatofibrosarcoma protuberans : Unusual chromosomal origin of the COL1A1-PDGFB fusion gene and synergistic effects of amplified regions in tumor development
- 2020
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Ingår i: Cancer Genetics. - : ELSEVIER SCIENCE INC. - 2210-7762 .- 2210-7770. ; 241, s. 34-41
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Tidskriftsartikel (refereegranskat)abstract
- The dermatofibrosarcoma protuberans family of tumors (DPFT) comprises cutaneous soft tissue neoplasms associated with aberrant PDGFBR signaling, typically through a COL1A1-PDGFB fusion. The aim of the present study was to obtain a better understanding of the chromosomal origin of this fusion and to assess the spectrum of secondary mutations at the chromosome and nucleotide levels. We thus investigated 42 tumor samples from 35 patients using chromosome banding, fluorescence in situ hybridization, single nucleotide polymorphism arrays, and/or massively parallel sequencing (gene panel, whole exome and transcriptome sequencing) methods. We confirmed the age-associated differences in the origin of the COL1A1-PDGFB fusion and could show that it in most cases must arise after DNA synthesis, i.e., in the S or G2 phase of the cell cycle. Whereas there was a non-random pattern of secondary chromosomal rearrangements, single nucleotide variants seem to have little impact on tumor progression. No clear genomic differences between low-grade and high-grade DPFT were found, but the number of chromosomes and chromosomal imbalances as well as the frequency of 9p deletions all tended to be greater among the latter. Gene expression profiling of tumors with COL1A1-PDGFB fusions associated with unbalanced translocations or ring chromosomes identified several transcriptionally up-regulated genes in the amplified regions of chromosomes 17 and 22, including TBX2, PRKCA, MSI2, SOX9, SOX10, and PRAME.
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