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Sökning: hsv:(MEDICIN OCH HÄLSOVETENSKAP) hsv:(Medicinska och farmaceutiska grundvetenskaper) hsv:(Medicinsk genetik) > Mertens Fredrik

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1.
  • Mandahl, Nils, et al. (författare)
  • Scattered genomic amplification in dedifferentiated liposarcoma
  • 2017
  • Ingår i: Molecular Cytogenetics. - : Springer Science and Business Media LLC. - 1755-8166. ; 10:1
  • 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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2.
  • Gisselsson Nord, David, et al. (författare)
  • Telomere dysfunction triggers extensive DNA fragmentation and evolution of complex chromosome abnormalities in human malignant tumors
  • 2001
  • Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 98:22, s. 12683-12688
  • Tidskriftsartikel (refereegranskat)abstract
    • Although mechanisms for chromosomal instability in tumors have been described in animal and in vitro models, little is known about these processes in man. To explore cytogenetic evolution in human tumors, chromosomal breakpoint profiles were constructed for 102 pancreatic carcinomas and 140 osteosarcomas, two tumor types characterized by extensive genomic instability. Cases with few chromosomal alterations showed a preferential clustering of breakpoints to the terminal bands, whereas tumors with many changes showed primarily interstitial and centromeric breakpoints. The terminal breakpoint frequency was negatively correlated to telomeric TTAGGG repeat length, and fluorescence in situ hybridization with telomeric TTAGGG probes consistently indicated shortened telomeres and >10% of chromosome ends lacking telomeric signals. Because telomeric dysfunction may lead to formation of unstable ring and dicentric chromosomes, mitotic figures were also evaluated. Anaphase bridges were found in all cases, and fluorescence in situ hybridization demonstrated extensive structural rearrangements of chromosomes, with terminal transferase detection showing fragmented DNA in 5-20% of interphase cells. Less than 2% of cells showed evidence of necrosis or apoptosis, and telomerase was expressed in the majority of cases. Telomeric dysfunction may thus trigger chromosomal fragmentation through persistent bridge-breakage events in pancreatic carcinomas and osteosarcomas, leading to a continuous reorganization of the tumor genome. Telomerase expression is not sufficient for completely stabilizing the chromosome complement but may be crucial for preventing complete genomic deterioration and maintaining cellular survival.
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3.
  • Möller, Emely, et al. (författare)
  • POU5F1, encoding a key regulator of stem cell pluripotency, is fused to EWSR1 in hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands
  • 2008
  • Ingår i: Journal of Pathology. - : Wiley. - 1096-9896 .- 0022-3417. ; 215:1, s. 78-86
  • Tidskriftsartikel (refereegranskat)abstract
    • The EWSR1 gene is known to play a crucial role in the development of a number of different bone and soft tissue tumours, notably Ewing's sarcoma. POU5F1 is expressed during early development to maintain the totipotent status of embryonic stem and germ cells. In the present study, we report the fusion of EWSR1 and POU5F1 in two types of epithelial tumours: hidradenoma of the skin and mucoepidermoid carcinoma of the salivary glands. This finding not only broadens considerably the spectrum of neoplasms associated with EWSR1 fusion genes but also strengthens the evidence for shared pathogenetic mechanisms in the development of adnexal and salivary gland tumours. Reminiscent of the previously reported fusion genes involving EWSR1, the identified transcript is predicted to encode a chimeric protein consisting of the EWSR1 amino-terminal domain and the POU5F1 carboxy-terminal domain. We assessed the transcriptional activation potential of the chimera compared to the wild-type proteins, as well as activation of transcription through the oct/sox composite element known to bind POU5F1. Among other POU5F1 target genes, this element is present in the promoter of NANOG and in the distal enhancer of POU5F1 itself. Our results show that although the chimera is capable of significant transcriptional activation, it may in fact convey a negative regulatory effect on target genes.
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4.
  • Adeyinka, Adewale, et al. (författare)
  • Comparative cytogenetic and DNA flow cytometric analysis of 242 primary breast carcinomas
  • 2003
  • Ingår i: Cancer Genetics and Cytogenetics. - 0165-4608. ; 147:1, s. 62-67
  • Tidskriftsartikel (refereegranskat)abstract
    • The cytogenetic and DNA flow cytometric findings in 242 breast carcinomas were compared. The combined use of both techniques improved the detection of abnormal cell populations from 65% by cytogenetic analysis alone and 59% by DNA flow cytometric analysis alone to 84%. Informative and comparable cytogenetic and flow cytometric data were obtained for 155 tumors. Among these 155 tumors, there was good concordance (64%) between the estimates of genomic changes by the two methods. Most discrepancies were among the DNA-diploid cases, where cytogenetic analysis detected small genomic changes. There were, however, also some exceptions in which large genomic changes detected by one method were missed by the other. Of the specific breast cancer-associated cytogenetic aberrations subjected to separate correlation analysis, polysomy for chromosome 20 was significantly associated with a high S-phase fraction, whereas loss of the long arm of chromosome 16 and/or the presence of a der(1;16) were significantly associated with a low S-phase fraction. Our data show that cytogenetic and DNA flow cytometric analyses of breast carcinomas give largely comparable results, and that combining data from both methods significantly improves the information obtained by either technique used alone on the genetic abnormalities in these tumors.
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5.
  • Al-Ibraheemi, Alyaa, et al. (författare)
  • Aberrant receptor tyrosine kinase signaling in lipofibromatosis : a clinicopathological and molecular genetic study of 20 cases
  • 2019
  • Ingår i: Modern Pathology. - : Elsevier BV. - 0893-3952. ; 32:3, s. 423-434
  • 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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6.
  • Anderson, William J., et al. (författare)
  • Superficial CD34-Positive Fibroblastic Tumor : A Clinicopathologic, Immunohistochemical, and Molecular Study of 59 Cases
  • 2022
  • Ingår i: American Journal of Surgical Pathology. - 0147-5185. ; 46:10, s. 1329-1339
  • Tidskriftsartikel (refereegranskat)abstract
    • Superficial CD34-positive fibroblastic tumor (SCD34FT) is a rare soft tissue neoplasm that shows overlapping features with PRDM10-rearranged soft tissue tumor (PRDM10-STT). This study characterizes the clinicopathologic, immunohistochemical, and molecular features of SCD34FT in a series of 59 cases. Fluorescence in situ hybridization to assess for PRDM10 rearrangement was performed in 12 tumors. Immunohistochemistry for CADM3 and WT1 was performed; CADM3 was also assessed in histologic mimics. Our cohort of 33 male and 26 female had a median age of 42 (range: 14 to 85) years. Tumors were most commonly located in the lower limb (73%), upper limb (8%), back (7%), and supraclavicular region (3%). The median tumor size was 3.0 cm (range: 1.0 to 9.0 cm). Clinical follow-up in 32 patients (median duration: 26 mo) revealed 2 local recurrences (6%). One patient developed regional lymph node metastases which were completely excised. Microscopically, SCD34FT comprised spindled and pleomorphic cells with glassy cytoplasm and occasional granular cell change. Fluorescence in situ hybridization confirmed PRDM10 rearrangement in 3/8 cases (38%). SCD34FT frequently expressed CADM3 (95%) and WT1 (75%). CADM3 was less diffusely positive in pleomorphic hyalinizing angiectatic tumor (40%), pleomorphic liposarcoma (20%), and undifferentiated pleomorphic sarcoma (10%). We corroborate that SCD34FT is indolent but may rarely metastasize to lymph nodes without adverse outcomes. CADM3 and WT1 may be useful in the distinction from histologic mimics. Since cases of SCD34FT with and without demonstrable PRDM10 rearrangement were clinicopathologically indistinguishable, our study further supports that SCD34FT and PRDM10-STT likely constitute a single entity.
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7.
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8.
  • Arbajian, Elsa, et al. (författare)
  • Deep sequencing of myxoinflammatory fibroblastic sarcoma
  • 2020
  • Ingår i: Genes, Chromosomes and Cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 59:5, s. 309-317
  • 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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9.
  • Arbajian, Elsa, et al. (författare)
  • In-depth genetic analysis of sclerosing epithelioid fibrosarcoma reveals recurrent genomic alterations and potential treatment targets
  • 2017
  • Ingår i: Clinical Cancer Research. - 1078-0432. ; 23:23, s. 7426-7434
  • 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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10.
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