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Book ; Thesis: Identifizierung des ursächlichen genetischen Defekts der Autosomal Dominanten Striatalen Degeneration (ADSD) durch positionelles Klonieren

Appenzeller, Silke

2008

Author's details	vorgelegt von Silke Appenzeller
Language	German
Size	VII, 125 S., Ill., graph. Darst.
Publishing country	Germany
Document type	Book ; Thesis
Thesis / German Habilitation thesis	Osnabrück, Univ., Diss., 2008
HBZ-ID	HT016366008
Database	Catalogue ZB MED Medicine, Health

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Article ; Online: Epithelioid and spindle cell rhabdomyosarcoma with EWSR1::TFCP2 fusion mimicking metastatic lung cancer: A case report and literature review.

Haug, Lukas / Doll, Julia / Appenzeller, Silke / Kunzmann, Volker / Rosenwald, Andreas / Maurus, Katja / Gerhard-Hartmann, Elena

Pathology, research and practice

2023 Volume 249, Page(s) 154779

Abstract: Rhabdomyosarcoma (RMS) with EWSR1/FUS::TFCP2 fusion is an emerging, molecularly defined, rare subtype of RMS. It can affect patients in a wide age range and follows an aggressive clinical course according to the reported cases. Due to its unusual ... ...

Abstract	Rhabdomyosarcoma (RMS) with EWSR1/FUS::TFCP2 fusion is an emerging, molecularly defined, rare subtype of RMS. It can affect patients in a wide age range and follows an aggressive clinical course according to the reported cases. Due to its unusual clinical and pathohistological features, with a typical intraosseous presentation and common cytokeratin expression, the diagnosis is challenging, and metastatic undifferentiated/sarcomatoid carcinoma can be an important differential diagnosis. We report here a case of a 55-year-old woman with an RMS with EWSR1::TFCP2 fusion mimicking metastatic lung cancer in view of the clinical and microscopic presentation. However, further molecular workup, including RNA sequencing, led to the proper diagnosis. Although these tumors are rare, knowledge of their unique features is essential for correct diagnosis as a basis for clinical management and optimization of therapeutic approaches.
MeSH term(s)	Female ; Humans ; Adult ; Child ; Middle Aged ; Rhabdomyosarcoma, Embryonal ; Lung Neoplasms/diagnosis ; Lung Neoplasms/genetics ; Rhabdomyosarcoma ; Carcinoma ; Diagnosis, Differential ; Transcription Factors/genetics ; RNA-Binding Protein EWS/genetics ; DNA-Binding Proteins
Chemical Substances	Transcription Factors ; EWSR1 protein, human ; RNA-Binding Protein EWS ; TFCP2 protein, human ; DNA-Binding Proteins
Language	English
Publishing date	2023-08-22
Publishing country	Germany
Document type	Review ; Case Reports
ZDB-ID	391889-0
ISSN	1618-0631 ; 0344-0338
ISSN (online)	1618-0631
ISSN	0344-0338
DOI	10.1016/j.prp.2023.154779
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Article ; Online: Circulating cell-free DNA-based biomarkers for prognostication and disease monitoring in adrenocortical carcinoma.

Lippert, Juliane / Smith, Gabrielle / Appenzeller, Silke / Landwehr, Laura-Sophie / Prete, Alessandro / Steinhauer, Sonja / Asia, Miriam / Urlaub, Hanna / Elhassan, Yasir S / Kircher, Stefan / Arlt, Wiebke / Fassnacht, Martin / Altieri, Barbara / Ronchi, Cristina L

European journal of endocrinology

2024 Volume 190, Issue 3, Page(s) 234–247

Abstract: Objective: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of ... ...

Abstract	Objective: Adrenocortical carcinoma (ACC) is a rare aggressive cancer with heterogeneous behaviour. Disease surveillance relies on frequent imaging, which comes with significant radiation exposure. The aim of the study was to investigate the role of circulating cell-free DNA (ccfDNA)-related biomarkers (BMs) for prognostication and monitoring of ACC. Design and methods: We investigated 34 patients with ACC and 23 healthy subjects (HSs) as controls. Circulating cell-free DNA was extracted by commercial kits and ccfDNA concentrations were quantified by fluorimeter (BM1). Targeted sequencing was performed using a customized panel of 27 ACC-specific genes. Leucocyte DNA was used to discriminate somatic variants (BM2), while tumour DNA was sequenced in 22/34 cases for comparison. Serial ccfDNA samples were collected during follow-up in 19 ACC patients (median period 9 months) and analysed in relationship with standard radiological imaging. Results: Circulating cell-free DNA concentrations were higher in ACC than HS (mean ± SD, 1.15 ± 1.56 vs 0.05 ± 0.05 ng/µL, P < .0001), 96% of them being above the cut-off of 0.146 ng/µL (mean HS + 2 SD, positive BM1). At ccfDNA sequencing, 47% of ACC showed at least 1 somatic mutation (positive BM2). A combined ccfDNA-BM score was strongly associated with both progression-free and overall survival (hazard ratio [HR] = 2.63; 95% CI, 1.13-6.13; P = .010, and HR = 5.98; 95% CI, 2.29-15.6; P = .0001, respectively). During disease monitoring, positive BM2 showed the best specificity (100%) and sensitivity (67%) to detect ACC recurrence or progress compared with BM1. Conclusion: ccfDNA-related BMs are frequently detected in ACC patients and represent a promising, minimally invasive tool to predict clinical outcome and complement surveillance imaging. Our findings will be validated in a larger cohort of ACCs with long-term follow-up.
MeSH term(s)	Humans ; Adrenocortical Carcinoma/diagnosis ; Adrenocortical Carcinoma/genetics ; Cell-Free Nucleic Acids/genetics ; Biomarkers ; DNA/genetics ; Adrenal Cortex Neoplasms/diagnosis ; Adrenal Cortex Neoplasms/genetics ; Biomarkers, Tumor/genetics
Chemical Substances	Cell-Free Nucleic Acids ; Biomarkers ; DNA (9007-49-2) ; Biomarkers, Tumor
Language	English
Publishing date	2024-03-07
Publishing country	England
Document type	Journal Article
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1093/ejendo/lvae022
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Article: Panel Sequencing of Primary Cutaneous B-Cell Lymphoma.

Wobser, Marion / Schummer, Patrick / Appenzeller, Silke / Kneitz, Hermann / Roth, Sabine / Goebeler, Matthias / Geissinger, Eva / Rosenwald, Andreas / Maurus, Katja

Cancers

2022 Volume 14, Issue 21

Abstract: Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin's lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low ... ...

Abstract	Background: Primary cutaneous follicular B-cell lymphoma (PCFBCL) represents an indolent subtype of Non-Hodgkin's lymphomas, being clinically characterized by slowly growing tumors of the skin and common cutaneous relapses, while only exhibiting a low propensity for systemic dissemination or fatal outcome. Up to now, only few studies have investigated underlying molecular alterations of PCFBCL with respect to somatic mutations. Objectives: Our aim was to gain deeper insight into the pathogenesis of PCFBCL and to delineate discriminatory molecular features of this lymphoma subtype. Methods: We performed hybridization-based panel sequencing of 40 lymphoma-associated genes of 10 cases of well-characterized PCFBCL. In addition, we included two further ambiguous cases of atypical B-cell-rich lymphoid infiltrate/B-cell lymphoma of the skin for which definite subtype attribution had not been possible by routine investigations. Results: In 10 out of 12 analyzed cases, we identified genetic alterations within 15 of the selected 40 target genes. The most frequently detected alterations in PCFBCL affected the Conclusions: To conclude, our molecular data support that PCFBCL shows distinct somatic mutations which may aid to differentiate PCFBCL from pseudo-lymphoma as well as from other indolent and aggressive cutaneous B-cell lymphomas. While the detected genetic alterations of PCFBCL did not turn out to harbor any prognostic value in our cohort, our molecular data may add adjunctive discriminatory features for diagnostic purposes on a molecular level.
Language	English
Publishing date	2022-10-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14215274
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Article ; Online: Plastin 3 rescues cell surface translocation and activation of TrkB in spinal muscular atrophy.

Hennlein, Luisa / Ghanawi, Hanaa / Gerstner, Florian / Palominos García, Eduardo / Yildirim, Ezgi / Saal-Bauernschubert, Lena / Moradi, Mehri / Deng, Chunchu / Klein, Teresa / Appenzeller, Silke / Sauer, Markus / Briese, Michael / Simon, Christian / Sendtner, Michael / Jablonka, Sibylle

The Journal of cell biology

2023 Volume 222, Issue 3

Abstract: Plastin 3 (PLS3) is an F-actin-bundling protein that has gained attention as a modifier of spinal muscular atrophy (SMA) pathology. SMA is a lethal pediatric neuromuscular disease caused by loss of or mutations in the Survival Motor Neuron 1 (SMN1) gene. ...

Abstract	Plastin 3 (PLS3) is an F-actin-bundling protein that has gained attention as a modifier of spinal muscular atrophy (SMA) pathology. SMA is a lethal pediatric neuromuscular disease caused by loss of or mutations in the Survival Motor Neuron 1 (SMN1) gene. Pathophysiological hallmarks are cellular maturation defects of motoneurons prior to degeneration. Despite the observed beneficial modifying effect of PLS3, the mechanism of how it supports F-actin-mediated cellular processes in motoneurons is not yet well understood. Our data reveal disturbed F-actin-dependent translocation of the Tropomyosin receptor kinase B (TrkB) to the cell surface of Smn-deficient motor axon terminals, resulting in reduced TrkB activation by its ligand brain-derived neurotrophic factor (BDNF). Improved actin dynamics by overexpression of hPLS3 restores membrane recruitment and activation of TrkB and enhances spontaneous calcium transients by increasing Cav2.1/2 "cluster-like" formations in SMA axon terminals. Thus, our study provides a novel role for PLS3 in supporting correct alignment of transmembrane proteins, a key mechanism for (moto)-neuronal development.
MeSH term(s)	Humans ; Actins/metabolism ; Carrier Proteins/metabolism ; Microfilament Proteins/genetics ; Microfilament Proteins/metabolism ; Motor Neurons/metabolism ; Muscular Atrophy, Spinal/genetics ; Muscular Atrophy, Spinal/pathology ; Survival of Motor Neuron 1 Protein/metabolism ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Receptor, trkB/metabolism
Chemical Substances	Actins ; Carrier Proteins ; Microfilament Proteins ; plastin ; Survival of Motor Neuron 1 Protein ; Membrane Proteins ; tropomyosin-related kinase-B, human (EC 2.7.10.1) ; Receptor, trkB (EC 2.7.10.1)
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	218154-x
ISSN	1540-8140 ; 0021-9525
ISSN (online)	1540-8140
ISSN	0021-9525
DOI	10.1083/jcb.202204113
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Article ; Online: Performance of DNA-based biomarkers for classification of adrenocortical carcinoma: a prognostic study.

Lippert, Juliane / Dischinger, Ulrich / Appenzeller, Silke / Prete, Alessandro / Kircher, Stefan / Skordilis, Kassiani / Elhassan, Yasir S / Altieri, Barbara / Fassnacht, Martin / Ronchi, Cristina L

European journal of endocrinology

2023 Volume 189, Issue 2, Page(s) 262–270

Abstract: Objective: Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve ... ...

Abstract	Objective: Adrenocortical carcinoma (ACC) is a rare aggressive malignancy with heterogeneous clinical outcomes. Recent studies proposed a combination of clinical/histopathological parameters (S-GRAS score) or molecular biomarkers (BMs) to improve prognostication. We performed a comparative analysis of DNA-based BMs by evaluating their added prognostic value to the S-GRAS score. Design and methods: A total of 194 formalin-fixed, paraffin-embedded (FFPE) ACC samples were analysed, including a retrospective training cohort (n = 107) and a prospective validation cohort (n = 87). Targeted DNA sequencing and pyrosequencing were used to detect somatic single-nucleotide variations in ACC-specific genes and methylation in the promoter region of paired box 5 (PAX5). The European Network for the Study of Adrenocortical Tumors (ENSAT) tumour stage, age, symptoms at presentation, resection status, and Ki-67 were combined to calculate S-GRAS. Endpoints were overall (OS), progression-free (PFS), and disease-free survival (DFS). Prognostic role was evaluated by multivariable survival analysis and their performance compared by Harrell's concordance index (C index). Results: In training cohort, an independent prognostic role was confirmed at multivariate analysis for two DNA-based BMs: alterations in Wnt/β-catenin and Rb/p53 pathways and hypermethylated PAX5 (both P< .05 for PFS and DFS, hazard ratio [HR] 1.47-2.33). These were combined to S-GRAS to obtain a combined (COMBI) score. At comparative analysis, the best discriminative prognostic model was COMBI score in both cohorts for all endpoints, followed by S-GRAS score (C index for OS 0.724 and 0.765, PFS 0.717 and 0.670, and DFS 0.699 and 0.644, respectively). Conclusions: Targeted DNA-based BM evaluated on routinely available FFPE samples improves prognostication of ACC beyond routinely available clinical and histopathological parameters. This approach may help to better individualise patient's management.
MeSH term(s)	Humans ; Adrenocortical Carcinoma/genetics ; Prognosis ; Retrospective Studies ; Adrenal Cortex Neoplasms/genetics ; Disease-Free Survival
Language	English
Publishing date	2023-08-17
Publishing country	England
Document type	Journal Article
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1093/ejendo/lvad112
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Article ; Online: Pontine autosomal dominant microangiopathy with leukoencephalopathy: Col4A1 gene variants in the original family and sporadic stroke.

Roos, Jessica / Müller, Stefanie / Giese, Anne / Appenzeller, Silke / Ringelstein, Erich Bernd / Fiehler, Jens / Berger, Klaus / Rolfs, Arndt / Hagel, Christian / Kuhlenbäumer, Gregor

Journal of neurology

2023 Volume 270, Issue 5, Page(s) 2631–2639

Abstract: Background: (1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene (COL4A1) ...

Abstract	Background: (1) Description of clinical and cranial MRI features in the original Pontine Autosomal Dominant Microangiopathy with Leukoencephalopathy (PADMAL) family and correlation with the segregation analysis of the causative collagen 4A1 gene (COL4A1) variant. (2) Sequence analysis of the COL4A1 miRNA-binding site containing the causative variant in two independent cross-sectional samples of sporadic stroke patients. Patients and methods: Sanger sequencing of the COL4A1 miRNA-binding site in the PADMAL family and 874 sporadic stroke patients. Results: PADMAL shows adult-onset usually between 30 and 50 years of age with initial brainstem-related symptoms most commonly dysarthria, with progression to dementia and tetraparesis. Radiologically pontine lacunes are followed by supratentorial white matter involvement. Radiological onset may precede clinical symptoms. We found no variants in the COL4A1 miRNA-binding site of sporadic stroke patients. Conclusion: Our results allow an early diagnosis of PADMAL based on cranial MRI, clinical signs, and confirmatory sequencing of the COL4A1 miRNA-29-binding site. COL4A1 miRNA-29-binding site variants do not contribute to a sizeable proportion of sporadic stroke.
MeSH term(s)	Adult ; Humans ; Cerebral Small Vessel Diseases/complications ; Cerebral Small Vessel Diseases/diagnostic imaging ; Cerebral Small Vessel Diseases/genetics ; Collagen Type IV/genetics ; Cross-Sectional Studies ; Leukoencephalopathies/diagnostic imaging ; Leukoencephalopathies/genetics ; MicroRNAs ; Mutation ; Stroke/complications ; Stroke/diagnostic imaging ; Stroke/genetics
Chemical Substances	COL4A1 protein, human ; Collagen Type IV ; MicroRNAs
Language	English
Publishing date	2023-02-14
Publishing country	Germany
Document type	Journal Article
ZDB-ID	187050-6
ISSN	1432-1459 ; 0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
ISSN (online)	1432-1459
ISSN	0340-5354 ; 0012-1037 ; 0939-1517 ; 1619-800X
DOI	10.1007/s00415-023-11590-9
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Article ; Online: Oncogenic Mutations and Gene Fusions in CD30-Positive Lymphoproliferations and Clonally Related Mycosis Fungoides Occurring in the Same Patients.

Wobser, Marion / Roth, Sabine / Appenzeller, Silke / Kneitz, Hermann / Goebeler, Matthias / Geissinger, Eva / Rosenwald, Andreas / Maurus, Katja

JID innovations

2021 Volume 1, Issue 3, Page(s) 100034

Abstract: The emergence of a common progenitor cell has been postulated for the association of CD30-positive lymphoproliferative disease (LPD) and mycosis fungoides (MF) within the same patient. Up to now, no comprehensive analysis has yet addressed the genetic ... ...

Abstract	The emergence of a common progenitor cell has been postulated for the association of CD30-positive lymphoproliferative disease (LPD) and mycosis fungoides (MF) within the same patient. Up to now, no comprehensive analysis has yet addressed the genetic profiles of such concurrent lymphoma subtypes. We aimed to delineate the molecular alterations of clonally related CD30-positive LPD and MF occurring in the same two patients. We analyzed the molecular profile of 16 samples of two patients suffering both from CD30-positive LPD and MF being obtained over a time course of at least 5 years. To detect oncogenic mutations, we applied targeted sequencing technologies with a hybrid capture-based DNA library preparation approach, and for the identification of fusion transcripts, an anchored multiplex PCR enrichment kit was used. In all samples of CD30-positive LPD and MF, oncogenic fusions afflicting the Jak/signal transducer and activator of transcription signaling pathway were present, namely
Language	English
Publishing date	2021-06-15
Publishing country	United States
Document type	Journal Article
ISSN	2667-0267
ISSN (online)	2667-0267
DOI	10.1016/j.xjidi.2021.100034
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Article: Targeted Deep Sequencing of Mycosis Fungoides Reveals Intracellular Signaling Pathways Associated with Aggressiveness and Large Cell Transformation.

Wobser, Marion / Roth, Sabine / Appenzeller, Silke / Houben, Roland / Schrama, David / Goebeler, Matthias / Geissinger, Eva / Rosenwald, Andreas / Maurus, Katja

Cancers

2021 Volume 13, Issue 21

Abstract: Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet.: Materials and ... ...

Abstract	Introduction: Large-cell transformation (LCT) of mycosis fungoides (MF) has been associated with a higher risk of relapse and progression and, consequently, restricted prognosis. Its molecular pathogenesis has not been elucidated yet. Materials and methods: In order to address molecular mechanisms of LCT, we performed hybrid capture panel-based sequencing of skin biopsies from 10 patients suffering from MF with LCT versus 17 patients without LCT including follow-up biopsies during clinical course, respectively (51 samples in total). The analyzed patients were attributed to three different groups based on the presence of LCT and clinical behavior. Results: While indolent MF cases without LCT did not show pathogenic driver mutations, a high rate of oncogenic alterations was detected in patients with LCT and aggressive clinical courses. Various genes of different oncogenic signaling pathways, including the MAPK and JAK-STAT signaling pathways, as well as epigenetic modifiers were affected. A high inter-individual and distinctive intra-individual mutation diversity was observed. Oncogenic RAS mutations were exclusively detected in patients with LCT. Conclusion: Our data demonstrate that LCT transition of MF is associated with increased frequency of somatic mutations in cancer-associated genes. In particular, the activation of RAS signaling-together with epigenetic dysregulation-may crucially contribute to the molecular pathogenesis of the LCT phenotype, thus conveying its adverse clinical behavior.
Language	English
Publishing date	2021-11-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13215512
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Article ; Online: A novel patient-derived cell line of adrenocortical carcinoma shows a pathogenic role of germline MUTYH mutation and high tumour mutational burden.

Landwehr, Laura-Sophie / Schreiner, Jochen / Appenzeller, Silke / Kircher, Stefan / Herterich, Sabine / Sbiera, Silviu / Fassnacht, Martin / Kroiss, Matthias / Weigand, Isabel

European journal of endocrinology

2021 Volume 184, Issue 6, Page(s) 823–835

Abstract: Background: The response of advanced adrenocortical carcinoma (ACC) to current chemotherapies is unsatisfactory and a limited rate of response to immunotherapy was observed in clinical trials. High tumour mutational burden (TMB) and the presence of a ... ...

Abstract	Background: The response of advanced adrenocortical carcinoma (ACC) to current chemotherapies is unsatisfactory and a limited rate of response to immunotherapy was observed in clinical trials. High tumour mutational burden (TMB) and the presence of a specific DNA signature are characteristic features of tumours with mutations in the gene MUTYH encoding the mutY DNA glycosylase. Both have been shown to potentially predict the response to immunotherapy. High TMB in an ACC cell line model has not been reported yet. Design and methods: The JIL-2266 cell line was established from a primary ACC tumour, comprehensively characterised and oxidative damage, caused by a dysfunctional mutY DNA glycosylase, confirmed. Results: Here, we characterise the novel patient-derived ACC cell line JIL-2266, which is deficient in mutY-dependent DNA repair. JIL-2266 cells have a consistent STR marker profile that confirmed congruousness with primary ACC tumour. Cells proliferate with a doubling time of 41 ± 13 h. Immunohistochemistry revealed positivity for steroidogenic factor-1. Mass spectrometry did not demonstrate significant steroid hormone synthesis. JIL-2266 have hemizygous mutations in the tumour suppressor gene TP53 (c.859G>T:p.E287X) and MUTYH (c.316C>T:p.R106W). Exome sequencing showed 683 single nucleotide variants and 4 insertions/deletions. We found increased oxidative DNA damage in the cell line and the corresponding primary tumour caused by impaired mutY DNA glycosylase function and accumulation of 8-oxoguanine. Conclusion: This model will be valuable as a pre-clinical ACC cell model with high TMB and a tool to study oxidative DNA damage in the adrenal gland.
MeSH term(s)	Adrenal Cortex Neoplasms/genetics ; Adrenal Cortex Neoplasms/pathology ; Adrenocortical Carcinoma/genetics ; Adrenocortical Carcinoma/pathology ; Cell Line, Tumor ; Cell Proliferation ; DNA Glycosylases/genetics ; Female ; Germ-Line Mutation ; Humans ; Middle Aged ; Tumor Burden ; Whole Exome Sequencing
Chemical Substances	DNA Glycosylases (EC 3.2.2.-) ; mutY adenine glycosylase (EC 3.2.2.-)
Language	English
Publishing date	2021-05-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1183856-5
ISSN	1479-683X ; 0804-4643
ISSN (online)	1479-683X
ISSN	0804-4643
DOI	10.1530/EJE-20-1423
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