141 results on '"Bens S."'
Search Results
2. Glial papillary tumour of the spinal cord with SMARCB1/INI1‐loss and favourable long‐term outcome
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Hasselblatt, M., Kurniawan, A. D., Rozsnoki, S., Johann, P. D., Bens, S., Oyen, F., Schneppenheim, R., Siebert, R., Capper, D., Kool, M., Schul, C., and Paulus, W.
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- 2018
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3. SPAG7 is a candidate gene for the periodic fever, aphthous stomatitis, pharyngitis and adenopathy (PFAPA) syndrome
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Bens, S, Zichner, T, Stütz, A M, Caliebe, A, Wagener, R, Hoff, K, Korbel, J O, von Bismarck, P, and Siebert, R
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- 2014
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4. Array-CGH: Erfahrungen aus Schleswig-Holstein
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Caliebe, A., Platzer, K., Argyriou, L., Bens, S., Hellenbroich, Y., Husemeyer, N., Nagel, I., Martin-Subero, J.I., Sporns, P., Stefanova, I., Tönnies, H., Vater, I., Weimer, J., Siebert, R., and Gillessen-Kaesbach, G.
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- 2012
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5. Zwischen Genomprogrammierung und genitalem Phänotyp: Der zweite Code der Androgene
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Bens, S., Ammerpohl, O., Siebert, R., and Holterhus, P.-M.
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- 2012
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6. Transienter neonataler Diabetes und Hypomethylierungssyndrome
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Bens, S., Siebert, R., and Caliebe, A.
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- 2010
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7. Genetic aberrations in pediatric follicular lymphoma: 36
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Martin-Guerrero, I, Salaverria, I, Burkhardt, B, Szczepanowski, M, Garcia-Orad, A, Pellissery, S, Bens, S, Mann, F, de Leval, L, Lisfeld, J, Klapper, W, Oschlies, I, and Siebert, R
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- 2012
8. Androgen Receptor Mutations Are Associated with Altered Epigenomic Programming as Evidenced by HOXA5 Methylation
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Bens, S., Ammerpohl, O., Martin-Subero, J.I., Appari, M., Richter, J., Hiort, O., Werner, R., Riepe, F.G., Siebert, R., and Holterhus, P.-M.
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- 2011
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9. COMPREHENSIVE EPIGENETIC AND TRANSCRIPTIONAL SURVEY OF THE “IMPRINTOME” IN NORMAL B-CELLS AND GERMINAL CENTER DERIVED B-CELL LYMPHOMAS OF THE MMML AND ICGC MMML-SEQ NETWORKS
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Bens, S., primary, Kolarova, J., additional, Kreuz, M., additional, Bernhart, S., additional, Kretzmer, H., additional, Wagener, R., additional, Küppers, R., additional, Ammerpohl, O., additional, Burkhardt, B., additional, Hoffmann, S., additional, Hummel, M., additional, Klapper, W., additional, Lichter, P., additional, Löffler, M., additional, Möller, P., additional, Radlwimmer, B., additional, Rosenstiel, P., additional, Stein, H., additional, Trümper, L., additional, and Siebert, R., additional
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- 2017
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10. Characterization of the genetic and epigenetic landscape of B‐cell neoplasms with IG::BCL3‐translocation.
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Drewes, C., López, C., Okeke, N., Hillebrecht, S., Schütz, P., Fischer, A., Mottok, A., Bens, S., Schneider, C., Stilgenbauer, S., Tausch, E., and Siebert, R.
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EPIGENETICS ,TUMORS ,IMMUNOGLOBULIN heavy chains - Abstract
In B-cell chronic lymphocytic leukaemia (CLL), the I IG i :: I BCL3 i translocation has been associated with younger age at diagnosis, a more aggressive clinical course and an atypical tumour cell phenotype [Michaux et al., 1997; Au et al., 2002]. Two distinct subsets of I IG i :: I BCL3 i translocation-positive B-cell neoplasms, differing in the number of chromosomal aberrations, IGHV mutation status and histopathology, have been described [Martín-Subero et al., 2007]. B Methods: b A total of 89 B-cell neoplasms with I IG i :: I BCL3 i translocation detected by fluorescence in situ hybridisation (FISH), including predominately cases diagnosed as CLL, were studied. [Extracted from the article]
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- 2023
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11. LACK OF SMARCB1 EXPRESSION CHARACTERIZES A SUBSET OF PERIPHERAL T‐CELL LYMPHOMAS ENRICHED IN CHILDREN AND YOUNG ADULTS.
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Fischer, A., Moreno, N., Interlandi, M., Albert, T. K., Mormann, J., Glaser, S., Patil, P., Balbach, S., Wagener, R., Bens, S., Dahlum, S., Göbel, C., Graf, M., Kremer, E., de Faria, F. W., Melcher, V., Hartmann, W., Herbrüggen, H., Robert, S., and Dugas, M.
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GENE expression ,YOUNG adults ,LYMPHOMAS ,T cells ,DNA analysis - Abstract
LACK OF SMARCB1 EXPRESSION CHARACTERIZES A SUBSET OF PERIPHERAL T-CELL LYMPHOMAS ENRICHED IN CHILDREN AND YOUNG ADULTS B Methods: b SMARCB1 (INI1) gene and protein expression was assessed in 315 patients with diverse mature T cell lymphomas by array-based mRNA profiling, immunohistochemistry and/or Western Blot. Comparison of the DNA methylome of human and murine PTCL-NOS SP Smarcb1- sp showed similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. [Extracted from the article]
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- 2023
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12. Incidence and genetic characterization of childhood acute lymphoblastic leukemia with CRLF2 overexpression treated according to the AIEOP-BFM ALL 2009 protocol
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Schmäh, J, primary, Fedders, B, additional, Zimmermann, M, additional, Dagdan, E, additional, Dörge, P, additional, Bens, S, additional, Moericke, A, additional, Alten, J, additional, Bleckmann, K, additional, Siebert, R, additional, Schrappe, M, additional, Stanulla, M, additional, and Cario, G, additional
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- 2015
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13. Recurrent loss of heterozygosity in 1p36 associated with TNFRSF14 mutations in IRF4 translocation negative pediatric follicular lymphomas
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Martin-Guerrero, I., primary, Salaverria, I., additional, Burkhardt, B., additional, Szczepanowski, M., additional, Baudis, M., additional, Bens, S., additional, de Leval, L., additional, Garcia-Orad, A., additional, Horn, H., additional, Lisfeld, J., additional, Pellissery, S., additional, Klapper, W., additional, Oschlies, I., additional, and Siebert, R., additional
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- 2013
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14. A Preliminary Genetic Map in Solea senegalensis (Pleuronectiformes, Soleidae) Using BAC-FISH and Next-Generation Sequencing
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García-Cegarra, A., primary, Merlo, M.A., additional, Ponce, M., additional, Portela-Bens, S., additional, Cross, I., additional, Manchado, M., additional, and Rebordinos, L., additional
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- 2013
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15. Array-CGH
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Caliebe, A., primary, Platzer, K., additional, Argyriou, L., additional, Bens, S., additional, Hellenbroich, Y., additional, Husemeyer, N., additional, Nagel, I., additional, Martin-Subero, J.I., additional, Sporns, P., additional, Stefanova, I., additional, Tönnies, H., additional, Vater, I., additional, Weimer, J., additional, Siebert, R., additional, and Gillessen-Kaesbach, G., additional
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- 2012
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16. ATRT-06. CLINICAL AND MOLECULAR RISK FACTORS IN CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMOUR (AT/RT) - EVIDENCE FROM THE EU-RHAB REGISTRY
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Fruehwald M, Hasselblatt M, Schneppenheim R, Nemes K, Bens S, Johan P, Hauser P, Quiroga E, PALMA SOLANO-PAEZ, Biassoni V, Mj, Gil-Da-Costa, and Graf N
17. Sellar region atypical teratoid/rhabdoid tumors (ATRT) in adults display DNA methylation profiles of the ATRT-MYC subgroup
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Rabea Wagener, Caterina Giannini, Jack M Raisanen, Michael C. Frühwald, Kazunori Arita, Florian Oyen, Gerald F. Reis, Guido Reifenberger, Stefan M. Pfister, Rolf Buslei, Martin Hasselblatt, Sumihito Nobusawa, Reiner Siebert, Reinhard Schneppenheim, Jörg Felsberg, David Capper, Pascal Johann, Werner Paulus, Arie Perry, Susanne Bens, Marcel Kool, Abbas Agaimy, Johann P.D., Bens S., Oyen F., Wagener R., Giannini C., Perry A., Raisanen J.M., Reis G.F., Nobusawa S., Arita K., Felsberg J., Reifenberger G., Agaimy A., Buslei R., Capper D., Pfister S.M., Schneppenheim R., Siebert R., Fruhwald M.C., Paulus W., Kool M., and Hasselblatt M.
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Adult ,Male ,Pathology ,medicine.medical_specialty ,Biology ,Compound heterozygosity ,pituitary ,Pathology and Forensic Medicine ,Epigenesis, Genetic ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,SMARCB1/INI1 ,Humans ,Point Mutation ,Age Factor ,Genetic Predisposition to Disease ,Pituitary Neoplasms ,Epigenetics ,Pituitary Neoplasm ,Allele ,SMARCB1 ,Rhabdoid Tumor ,Aged ,medicine.diagnostic_test ,Point mutation ,Age Factors ,Teratoma ,atypical teratoid/rhabdoid tumor ,SMARCB1 Protein ,DNA Methylation ,Middle Aged ,medicine.disease ,Phenotype ,030220 oncology & carcinogenesis ,DNA methylation ,Atypical teratoid rhabdoid tumor ,outcome ,DNA methylation profiling ,Surgery ,Female ,Anatomy ,030217 neurology & neurosurgery ,Gene Deletion ,Fluorescence in situ hybridization ,Human - Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly encountered in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. A small group of ATRT stands out clinically, because these tumors are located in the sellar region of adults. To investigate if sellar region ATRT in adults represents a molecular distinct entity, we characterized molecular alterations in 7 sellar region ATRTs in adults as compared with 150 pediatric ATRTs and 47 pituitary adenomas using SMARCB1 sequencing, multiplex ligation-dependent probe amplification and fluorescence in situ hybridization as well as DNA methylation profiling. The median age of the 6 female and 1 male patients was 56 years. On histopathologic examination, all tumors were malignant rhabdoid tumors showing loss of SMARCB1/INI1 protein expression. Two cases displayed compound heterozygous SMARCB1 point mutations, 3 cases showed heterozygous SMARCB1 deletions with point mutations of the other allele and 1 case a homozygous SMARCB1 deletion; in 1 case, underlying SMARCB1 alterations could not be identified. On unsupervised hierarchical cluster analysis of DNA methylation profiles, sellar region ATRTs did not form a distinct group, but clustered with ATRT-MYC, 1 of 3 recently described molecular subgroups of ATRT. On analysis of DNA methylation array intensity data, only 1 sellar region ATRT showed characteristic features of pediatric ATRT-MYC, that is, major copy number losses affecting the SMARCB1 region. In conclusion, these results suggest that sellar region ATRTs in adults form a clinically distinct entity with a different mutational spectrum, but epigenetic similarities with pediatric ATRTs of the ATRT-MYC subgroup.
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- 2020
18. Desmoplastic myxoid tumor, SMARCB1-mutant: clinical, histopathological and molecular characterization of a pineal region tumor encountered in adolescents and adults
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Werner Paulus, Martin Sill, Annika K. Wefers, Susanne Bens, Fanny Burel-Vandenbos, Christian Thomas, Michael C. Frühwald, Torsten Pietsch, Francesca Brett, Florian Oyen, Abbas Agaimy, Marcel Kool, Karolina Nemes, Silke Vogelgesang, Guido Reifenberger, Frantz Rom Poulsen, Reiner Siebert, Fausto J. Rodriguez, Roger E. McLendon, Caterina Giannini, Pascal Johann, Eric S. Lipp, Stefan Tippelt, Kathy Keyvani, Klaus Kuchelmeister, Martin Hasselblatt, Andreas von Deimling, Uwe Kordes, Istvan Bodi, Thomas C., Wefers A., Bens S., Nemes K., Agaimy A., Oyen F., Vogelgesang S., Rodriguez F.J., Brett F.M., McLendon R., Bodi I., Burel-Vandenbos F., Keyvani K., Tippelt S., Poulsen F.R., Lipp E.S., Giannini C., Reifenberger G., Kuchelmeister K., Pietsch T., Kordes U., Siebert R., Fruhwald M.C., Johann P.D., Sill M., Kool M., von Deimling A., Paulus W., and Hasselblatt M.
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0301 basic medicine ,Adult ,Male ,Pathology ,medicine.medical_specialty ,Proliferation index ,Adolescent ,Medizin ,Brain tumor ,Biology ,Pineal Gland ,Pathology and Forensic Medicine ,Frameshift mutation ,Cohort Studies ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Young Adult ,0302 clinical medicine ,Atypical teratoid/rhabdoid tumor (ATRT), myxoid stroma, pineal region ,medicine ,Humans ,SMARCB1 ,Rhabdoid Tumor ,Brain Neoplasms ,Myxoid tumor ,Age Factors ,SMARCB1 Protein ,Middle Aged ,medicine.disease ,Survival Rate ,030104 developmental biology ,Tumor progression ,Atypical teratoid rhabdoid tumor ,Mutation ,Atypical teratoid/rhabdoid tumor, SMARCB1 gene, pineal ,Female ,Neurology (clinical) ,Epithelioid cell ,030217 neurology & neurosurgery - Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant brain tumor predominantly occurring in infants. Mutations of the SMARCB1 gene are the characteristic genetic lesion. SMARCB1-mutant tumors in adolescents and adults are rare and may show uncommon histopathological and clinical features. Here we report seven SMARCB1-deficient intracranial tumors sharing distinct clinical, histopathological and molecular features. Median age of the four females and three males was 40years (range 15–61years). All tumors were located in the pineal region. Histopathologically, these tumors displayed spindled and epithelioid cells embedded in a desmoplastic stroma alternating with a variable extent of a loose myxoid matrix. All cases showed loss of nuclear SMARCB1/INI1 protein expression, expression of EMA and CD34 was frequent and the Ki67/MIB1 proliferation index was low in the majority of cases (median 3%). Three cases displayed heterozygous SMARCB1 deletions and two cases a homozygous SMARCB1 deletion. On sequencing, one tumor showed a 2bp deletion in exon 4 (c.369_370del) and one a short duplication in exon 3 (c.237_276dup) both resulting in frameshift mutations. Most DNA methylation profiles were not classifiable using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-SNE analysis and hierarchical clustering analysis, however, all tumors grouped closely together and showed similarities with ATRT-MYC. After a median observation period of 48months, three patients were alive with stable disease, whereas one patient experienced tumor progression and three patients had succumbed to disease. In conclusion, our series represents an entity with distinct clinical, histopathological and molecular features showing epigenetic similarities with ATRT-MYC. We propose the designation desmoplastic myxoid tumor (DMT), SMARCB1-mutant, for these tumors.
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- 2020
19. Molecular switch from MYC to MYCN expression in MYC protein negative Burkitt lymphoma cases
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Leonardo Del Porro, Reiner Siebert, Lucia Mundo, Joshua Nyagol, Stefano Lazzi, Noel Onyango, Isaac Ndede, Mohsen Navari, Robert B. Russell, Nicholas Othieno Abinya, Roshanak Bob, Cristina López, Virginia Mancini, Harald Stein, Bruno Jim Rocca, Kirkita Patel, Massimo Granai, Maria Margherita De Santi, Maria Raffaella Ambrosio, Susanne Bens, Francesco Raimondi, Lorenzo Leoncini, Raffaella Guazzo, Pier Paolo Piccaluga, Mundo, L., Ambrosio, M. R., Raimondi, F., Del Porro, L., Guazzo, R., Mancini, V., Granai, M., Jim Rocca, B., Lopez, C., Bens, S., Onyango, N., Nyagol, J., Abinya, N., Navari, M., Ndede, I., Patel, K., Paolo Piccaluga, P., Bob, R., de Santi, M. M., Russell, R. B., Lazzi, S., Siebert, R., Stein, H., and Leoncini, L.
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Adult ,Male ,Models, Molecular ,Adolescent ,Lymphoma ,Protein Conformation ,Genes, myc ,Biology ,medicine.disease_cause ,lcsh:RC254-282 ,Translocation, Genetic ,Article ,Immunophenotyping ,Proto-Oncogene Proteins c-myc ,Structure-Activity Relationship ,Young Adult ,Neoplasms ,Neuroblastoma ,medicine ,Humans ,Gene family ,RNA, Messenger ,Child ,neoplasms ,Gene ,MYC Gene Rearrangement ,Aged ,Neoplasms, Proto-Oncogene Proteins c-myc, Human cancers ,Regulation of gene expression ,Haematological cancer ,Mutation ,Human cancers ,Oncogene ,High-Throughput Nucleotide Sequencing ,Genomics ,Hematology ,Middle Aged ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Burkitt Lymphoma ,Immunohistochemistry ,Gene Expression Regulation, Neoplastic ,Oncology ,Cancer research ,Female ,N-Myc ,Genes, Switch - Abstract
MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization.
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- 2019
20. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma
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Peter Nürnberg, German Ott, Grzegorz Rymkiewicz, Francesco Raimondi, Heike Horn, Lorenzo Leoncini, Reiner Siebert, Rabea Wagener, Daniel Hübschmann, Janine Altmüller, Inga Nagel, Elaine S. Jaffe, Kortine Kleinheinz, Matthias Schlesner, Birgit Burkhardt, Wolfram Klapper, Robert B. Russell, Julian Seufert, Susanne Bens, Holger Thiele, Rex Au-Yeung, Christian W. Kohler, Wagener, R., Seufert, J., Raimondi, F., Bens, S., Kleinheinz, K., Nagel, I., Ller, J. A., Thiele, H., Hubschmann, D., Kohler, C. W., Nurnberg, P., Au-Yeung, R., Burkhardt, B., Horn, H., Leoncini, L., Jaffe, E. S., Ott, G., Rymkiewicz, G., Schlesner, M., Russell, R. B., Klapper, W., and Siebert, R.
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Adult ,Male ,Adolescent ,Immunology ,Chromosomal translocation ,Biology ,medicine.disease_cause ,Biochemistry ,Proto-Oncogene Proteins c-myc ,Young Adult ,hemic and lymphatic diseases ,medicine ,Biomarkers, Tumor ,Humans ,ddc:610 ,Child ,Gene ,11q Aberration ,Retrospective Studies ,Genetics ,Chromosome Aberrations ,Mutation ,Chromosomes, Human, Pair 11 ,DNA Helicases ,Chromosome ,Cell Biology ,Hematology ,Middle Aged ,medicine.disease ,Prognosis ,GNA13 ,Burkitt Lymphoma ,Lymphoma ,DNA-Binding Proteins ,Child, Preschool ,ATPases Associated with Diverse Cellular Activities ,Female ,Burkitt's lymphoma ,Follow-Up Studies - Abstract
The new recently described provisional lymphoma category Burkitt-like lymphoma with 11q aberration comprises cases similar to Burkitt lymphoma (BL) on morphological, immunophenotypic and gene-expression levels but lacking the IG-MYC translocation. They are characterized by a peculiar imbalance pattern on chromosome 11, but the landscape of mutations is not yet described. Thus, we investigated 15 MYC-negative Burkitt-like lymphoma with 11q aberration (mnBLL,11q,) cases by copy-number analysis and whole-exome sequencing. We refined the regions of 11q imbalance and identified the INO80 complex-associated gene NFRKB as a positional candidate in 11q24.3. Next to recurrent gains in 12q13.11-q24.32 and 7q34-qter as well as losses in 13q32.3-q34, we identified 47 genes recurrently affected by protein-changing mutations (each ≥3 of 15 cases). Strikingly, we did not detect recurrent mutations in genes of the ID3-TCF3 axis or the SWI/SNF complex that are frequently altered in BL, or in genes frequently mutated in germinal center–derived B-cell lymphomas like KMT2D or CREBBP. An exception is GNA13, which was mutated in 7 of 15 cases. We conclude that the genomic landscape of mnBLL,11q, differs from that of BL both at the chromosomal and mutational levels. Our findings implicate that mnBLL,11q, is a lymphoma category distinct from BL at the molecular level.
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- 2019
21. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis
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Pascal Johann, Yvonne Crede, Nasir Ud Din, Frank van Landeghem, Volker Hovestadt, David Capper, Annika K. Wefers, Susanne Peetz-Dienhart, Felice Giangaspero, Marcel Kool, Arie Perry, Daniel Schrimpf, Manila Antonelli, Reiner Siebert, Markus J. Riemenschneider, Stefan M. Pfister, David Sumerauer, Hannes Vogel, Christian Thomas, Michael C. Frühwald, Florian Oyen, Caterina Giannini, Susanne Bens, Andrey Korshunov, Peter Hauser, Reinhard Schneppenheim, David T.W. Jones, Marie Christine Bernardo, Kathy Keyvani, Martin Hasselblatt, Hasselblatt M., Thomas C., Hovestadt V., Schrimpf D., Johann P., Bens S., Oyen F., Peetz-Dienhart S., Crede Y., Wefers A., Vogel H., Riemenschneider M.J., Antonelli M., Giangaspero F., Bernardo M.C., Giannini C., Ud Din N., Perry A., Keyvani K., van Landeghem F., Sumerauer D., Hauser P., Capper D., Korshunov A., Jones D.T.W., Pfister S.M., Schneppenheim R., Siebert R., Fruhwald M.C., and Kool M.
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tumors ,Male ,DNA Copy Number Variations ,Prognosi ,neurology (clinical) ,SMARCB1 ,cellular and molecular neuroscience ,chordomas ,skull base and spine ,Medizin ,Pathology and Forensic Medicine ,Brain Neoplasm ,Diagnosis, Differential ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,medicine ,Biomarkers, Tumor ,Chordoma ,Cluster Analysis ,Humans ,Child ,Rhabdoid Tumor ,Molecular entity ,DNA Copy Number Variation ,Cluster Analysi ,business.industry ,Brain Neoplasms ,Poorly differentiated ,SMARCB1 Protein ,Teratoma ,Infant ,DNA Methylation ,medicine.disease ,Prognosis ,Smarcb1 ini1 ,Survival Analysis ,030220 oncology & carcinogenesis ,Child, Preschool ,Cancer research ,Female ,Neurology (clinical) ,Survival Analysi ,Differential diagnosis ,business ,030217 neurology & neurosurgery ,Human - Abstract
Lettera no abstract
- Published
- 2016
22. Constitutional mosaicism of pathogenic variants in SMARCB1 in a subset of patients with sporadic rhabdoid tumors.
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Fleischmann LS, Nemes K, Glaser S, Kouroukli AG, Boros M, Bens S, Dahlum S, Kretzmer H, Oyen F, Gerss J, Hasselblatt M, Frühwald MC, and Siebert R
- Abstract
Background: Malignant rhabdoid tumors are aggressive malignancies predominantly affecting very young children. The characteristic genetic alteration is biallelic inactivation of SMARCB1. In approximately 30% of patients one SMARCB1 allele is constitutionally altered conferring a particularly unfavourable prognosis. Constitutional mosaicism for pathogenic SMARCB1 mutations has recently been reported in distinct cases of allegedly sporadic rhabdoid tumors. We aimed to systematically investigate the frequency and clinical impact of constitutional mosaicism in patients with sporadic rhabdoid tumors included in the EU-RHAB registry., Methods: We selected 29 patients with rhabdoid tumors displaying at least one pathogenic small variant in SMARCB1 in the tumor DNA and absence of a germline mutation. We re-screened blood-derived patient and control DNA for the respective small variant by PCR with unique molecular identifiers and ultra-deep next generation sequencing. Clinical data in patients with and without mosaicism and 174 EU-RHAB controls were compared., Results: Employing an ultra-deep sequencing approach, we detected tumor-associated SMARCB1 variants in blood-derived DNA in 9/29 patients. In 6/29 patients (21%), whose variant allele frequency (VAF) exceeded 2%, constitutional mosaicism was assumed whereas tumor DNA contamination was documented in 1/3 patients with VAF below 1%. No significant differences were observed between 6 mosaic-positive and 20 -negative patients regarding age at diagnosis, presence of metastases, event-free or overall survival., Conclusion: Constitutional mosaicism for pathogenic small SMARCB1 variants is recurrent in patients with allegedly sporadic rhabdoid tumors. The clinical implications of such variants need to be determined in larger, prospective cohorts also including detection of structural variants of SMARCB1., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)
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- 2024
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23. Targeting oncogenic TERT promoter variants by allele-specific epigenome editing.
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Kouroukli AG, Rajaram N, Bashtrykov P, Kretzmer H, Siebert R, Jeltsch A, and Bens S
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- Humans, Alleles, DNA Methylation, Epigenome, RNA, Guide, CRISPR-Cas Systems, Promoter Regions, Genetic, Nucleotides, Mutation, Lung Neoplasms, Telomerase genetics
- Abstract
Background: Activation of dominant oncogenes by small or structural genomic alterations is a common driver mechanism in many cancers. Silencing of such dominantly activated oncogenic alleles, thus, is a promising strategy to treat cancer. Recently, allele-specific epigenome editing (ASEE) has been described as a means to reduce transcription of genes in an allele-specific manner. In cancer, specificity to an oncogenic allele can be reached by either targeting directly a pathogenic single-nucleotide variant or a polymorphic single-nucleotide variant linked to the oncogenic allele. To investigate the potential of ASEE in cancer, we here explored this approach by targeting variants at the TERT promoter region. The TERT promoter region has been described as one of the most frequently mutated non-coding cancer drivers., Results: Sequencing of the TERT promoter in cancer cell lines showed 53% (41/77) to contain at least one heterozygous sequence variant allowing allele distinction. We chose the hepatoblastoma cell line Hep-G2 and the lung cancer cell line A-549 for this proof-of-principle study, as they contained two different kinds of variants, namely the activating mutation C228T in the TERT core promoter and the common SNP rs2853669 in the THOR region, respectively. These variants were targeted in an allele-specific manner using sgRNA-guided dCas9-DNMT3A-3L complexes. In both cell lines, we successfully introduced DNA methylation specifically to the on-target allele of the TERT promoter with limited background methylation on the off-target allele or an off-target locus (VEGFA), respectively. We observed a maximum CpG methylation gain of 39% and 76% on the target allele when targeting the activating mutation and the common SNP, respectively. The epigenome editing translated into reduced TERT RNA expression in Hep-G2., Conclusions: We applied an ASEE-mediated approach to silence TERT allele specifically. Our results show that the concept of dominant oncogene inactivation by allele-specific epigenome editing can be successfully translated into cancer models. This new strategy may have important advantages in comparison with existing therapeutic approaches, e.g., targeting telomerase, especially with regard to reducing adverse side effects., (© 2023. The Author(s).)
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- 2023
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24. Development of super-specific epigenome editing by targeted allele-specific DNA methylation.
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Rajaram N, Kouroukli AG, Bens S, Bashtrykov P, and Jeltsch A
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- Humans, Epigenesis, Genetic, Alleles, HEK293 Cells, Epigenome, CRISPR-Cas Systems, Gene Editing, DNA Methylation, RNA, Guide, CRISPR-Cas Systems
- Abstract
Background: Epigenome editing refers to the targeted reprogramming of genomic loci using an EpiEditor which may consist of an sgRNA/dCas9 complex that recruits DNMT3A/3L to the target locus. Methylation of the locus can lead to a modulation of gene expression. Allele-specific DNA methylation (ASM) refers to the targeted methylation delivery only to one allele of a locus. In the context of diseases caused by a dominant mutation, the selective DNA methylation of the mutant allele could be used to repress its expression but retain the functionality of the normal gene., Results: To set up allele-specific targeted DNA methylation, target regions were selected from hypomethylated CGIs bearing a heterozygous SNP in their promoters in the HEK293 cell line. We aimed at delivering maximum DNA methylation with highest allelic specificity in the targeted regions. Placing SNPs in the PAM or seed regions of the sgRNA, we designed 24 different sgRNAs targeting single alleles in 14 different gene loci. We achieved efficient ASM in multiple cases, such as ISG15, MSH6, GPD1L, MRPL52, PDE8A, NARF, DAP3, and GSPT1, which in best cases led to five to tenfold stronger average DNA methylation at the on-target allele and absolute differences in the DNA methylation gain at on- and off-target alleles of > 50%. In general, loci with the allele discriminatory SNP positioned in the PAM region showed higher success rate of ASM and better specificity. Highest DNA methylation was observed on day 3 after transfection followed by a gradual decline. In selected cases, ASM was stable up to 11 days in HEK293 cells and it led up to a 3.6-fold change in allelic expression ratios., Conclusions: We successfully delivered ASM at multiple genomic loci with high specificity, efficiency and stability. This form of super-specific epigenome editing could find applications in the treatment of diseases caused by dominant mutations, because it allows silencing of the mutant allele without repression of the expression of the normal allele thereby minimizing potential side-effects of the treatment., (© 2023. BioMed Central Ltd., part of Springer Nature.)
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- 2023
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25. Rhabdoid tumors in patients conceived following ART: is there an association?
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Nemes K, Benesch M, Kolarova J, Johann P, Hasselblatt M, Thomas C, Bens S, Glaser S, Ammerpohl O, Liaugaudiene O, Sadeghipour A, von der Weid N, Schmid I, Gidding C, Erdreich-Epstein A, Khurana C, Ebetsberger-Dachs G, Lemmer A, Khatib Z, Hernández Marqués C, Pears J, Quehenberger F, Kordes U, Vokuhl C, Gerss J, Schwarz H, Bison B, Biegel JA, Siebert R, and Frühwald MC
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- Humans, Female, Male, Retrospective Studies, Infant, Child, Preschool, Child, DNA Methylation, SMARCB1 Protein genetics, Infant, Newborn, Rhabdoid Tumor genetics
- Abstract
Study Question: In children affected by rhabdoid tumors (RT), are there clinical, therapeutic, and/or (epi-)genetic differences between those conceived following ART compared to those conceived without ART?, Summary Answer: We detected a significantly elevated female predominance, and a lower median age at diagnosis, of children with RT conceived following ART (RT_ART) as compared to other children with RT., What Is Known Already: Anecdotal evidence suggests an association of ART with RT., Study Design, Size, Duration: This was a multi-institutional retrospective survey. Children with RT conceived by ART were identified in our EU-RHAB database (n = 11/311 children diagnosed between January 2010 and January 2018) and outside the EU-RHAB database (n = 3) from nine different countries. A population-representative German EU-RHAB control cohort of children with RTs conceived without ART (n = 211) (EU-RHAB control cohort) during the same time period was used as a control cohort for clinical, therapeutic, and survival analyses. The median follow-up time was 11.5 months (range 0-120 months) for children with RT_ART and 18.5 months (range 0-153 months) for the EU-RHAB control cohort., Participants/materials, Setting, Methods: We analyzed 14 children with RT_ART diagnosed from January 2010 to January 2018. We examined tumors and matching blood samples for SMARCB1 mutations and copy number alterations using FISH, multiplex ligation-dependent probe amplification, and DNA sequencing. DNA methylation profiling of tumor and/or blood samples was performed using DNA methylation arrays and compared to respective control cohorts of similar age (n = 53 tumors of children with RT conceived without ART, and n = 38 blood samples of children with no tumor born small for gestational age)., Main Results and the Role of Chance: The median age at diagnosis of 14 individuals with RT_ART was 9 months (range 0-66 months), significantly lower than the median age of patients with RT (n = 211) in the EU-RHAB control cohort (16 months (range 0-253), P = 0.03). A significant female predominance was observed in the RT_ART cohort (M:F ratio: 2:12 versus 116:95 in EU-RHAB control cohort, P = 0.004). Eight of 14 RT_ART patients were diagnosed with atypical teratoid rhabdoid tumor, three with extracranial, extrarenal malignant rhabdoid tumor, one with rhabdoid tumor of the kidney and two with synchronous tumors. The location of primary tumors did not differ significantly in the EU-RHAB control cohort (P = 0.27). Six of 14 RT_ART patients presented with metastases at diagnosis. Metastatic stage was not significantly different from that within the EU-RHAB control cohort (6/14 vs 88/211, P = 1). The incidence of pathogenic germline variants was five of the 12 tested RT_ART patients and, thus, not significantly different from the EU-RHAB control cohort (5/12 versus 36/183 tested, P = 0.35). The 5-year overall survival (OS) and event free survival (EFS) rates of RT_ART patients were 42.9 ± 13.2% and 21.4 ± 11%, respectively, and thus comparable to the EU-RHAB control cohort (OS 41.1 ± 3.5% and EFS 32.1 ± 3.3). We did not find other clinical, therapeutic, outcome factors distinguishing patients with RT_ART from children with RTs conceived without ART (EU-RHAB control cohort). DNA methylation analyses of 10 tumors (atypical teratoid RT = 6, extracranial, extrarenal malignant RT = 4) and six blood samples from RT_ART patients showed neither evidence of a general DNA methylation difference nor underlying imprinting defects, respectively, when compared to a control group (n = 53 RT samples of patients without ART, P = 0.51, n = 38 blood samples of patients born small for gestational age, P = 0.1205)., Limitations, Reasons for Caution: RTs are very rare malignancies and our results are based on a small number of children with RT_ART., Wider Implications of the Findings: This cohort of patients with RT_ART demonstrated a marked female predominance, and a rather low median age at diagnosis even for RTs. Other clinical, treatment, outcome, and molecular factors did not differ from those conceived without ART (EU-RHAB control cohort) or reported in other series, and there was no evidence for imprinting defects. Long-term survival is achievable even in cases with pathogenic germline variants, metastatic disease at diagnosis, or relapse. The female preponderance among RT_ART patients is not yet understood and needs to be evaluated, ideally in larger international series., Study Funding/competing Interest(s): M.C.F. is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.10, by the 'Deutsche Forschungsgemeinschaft' DFG FR 1516/4-1 and by the Deutsche Krebshilfe 70113981. R.S. received grant support by Deutsche Krebshilfe 70114040 and for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen. P.D.J. is supported by the Else-Kroener-Fresenius Stiftung and receives a Max-Eder scholarship from the Deutsche Krebshilfe. M.H. is supported by DFG (HA 3060/8-1) and IZKF Münster (Ha3/017/20). BB is supported by the 'Deutsche Kinderkrebsstiftung' DKS 2020.05. We declare no competing interests., Trial Registration Number: N/A., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
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- 2023
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26. PI3K/AKT inhibitor BEZ-235 targets CCND2 and induces G1 arrest in breast implant-associated anaplastic large cell lymphoma.
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Nagel S, Fischer A, Bens S, Hauer V, Pommerenke C, Uphoff CC, Zaborski M, Siebert R, and Quentmeier H
- Abstract
Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a mature, CD30-positive T-cell lymphoma lacking expression of the anaplastic lymphoma kinase (ALK). In contrast to ALK-positive ALCL, BIA-ALCL cells express cyclin D2 (CCND2) which controls cyclin dependent kinases 4 and 6 (CDK4/6). DNA methylation and expression analyses performed with cell lines and primary cells suggest that the expression of CCND2 in BIA-ALCL cell lines conforms to the physiological status of differentiated T-cells, and that it is not the consequence of genomic alterations as observed in other hematopoietic tumors. Using cell line model systems we show that treatment with the CDK4/6 inhibitor palbociclib effects dephosphorylation of the retinoblastoma protein (RB) and causes cell cycle arrest in G1 in BIA-ALCL. Moreover, we show that the PI3K/AKT inhibitor BEZ-235 induces dephosphorylation of the mTORC1 target S6 and of GSK3β, indicators for translational inhibition and proteasomal degradation. Consequently, CCND2 protein levels declined after stimulation with BEZ-235, RB was dephosphorylated and the cell cycle was arrested in G1. Taken together, our data imply potential application of CDK4/6 inhibitors and PI3K/AKT inhibitors for the therapy of BIA-ALCL., Competing Interests: Declaration of Competing Interest The authors declare no competing interests. Competing Interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
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- 2023
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27. Recurrent atypical teratoid/rhabdoid tumors (AT/RT) reveal discrete features of progression on histology, epigenetics, copy number profiling, and transcriptomics.
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Johann PD, Altendorf L, Efremova EM, Holsten T, Steinbügl M, Nemes K, Eckhardt A, Kresbach C, Bockmayr M, Koch A, Haberler C, Antonelli M, DeSisto J, Schuhmann MU, Hauser P, Siebert R, Bens S, Kool M, Green AL, Hasselblatt M, Frühwald MC, and Schüller U
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- Child, Child, Preschool, Female, Humans, Infant, Male, Chromosomes, Human, Pair 1 genetics, Chromosomes, Human, Pair 10 genetics, Cohort Studies, Dendritic Cells, DNA Methylation, Histology, Mitosis, Sequence Analysis, RNA, Transcription Factors genetics, Gene Expression Regulation, Neoplastic genetics, Disease Progression, DNA Copy Number Variations genetics, Epigenesis, Genetic, Gene Expression Profiling, Recurrence, Rhabdoid Tumor classification, Rhabdoid Tumor genetics, Rhabdoid Tumor immunology, Rhabdoid Tumor pathology, Teratoma classification, Teratoma genetics, Teratoma immunology, Teratoma pathology
- Abstract
Atypical teratoid/rhabdoid tumors (AT/RT) are the most common malignant brain tumors manifesting in infancy. They split into four molecular types. The major three (AT/RT-SHH, AT/RT-TYR, and AT/RT-MYC) all carry mutations in SMARCB1, the fourth quantitatively smaller type is characterized by SMARCA4 mutations (AT/RT-SMARCA4). Molecular characteristics of disease recurrence or metastatic spread, which go along with a particularly dismal outcome, are currently unclear. Here, we investigated tumor tissue from 26 patients affected by AT/RT to identify signatures of recurrences in comparison with matched primary tumor samples. Microscopically, AT/RT recurrences demonstrated a loss of architecture and significantly enhanced mitotic activity as compared to their related primary tumors. Based on DNA methylation profiling, primary tumor and related recurrence were grossly similar, but three out of 26 tumors belonged to a different molecular type or subtype after second surgery compared to related primary lesions. Copy number variations (CNVs) differed in six cases, showing novel gains on chromosome 1q or losses of chromosome 10 in recurrences as the most frequent alterations. To consolidate these observations, our cohort was combined with a data set of unmatched primary and recurrent AT/RT, which demonstrated chromosome 1q gain and 10 loss in 18% (n = 7) and 11% (n = 4) of the recurrences (n = 38) as compared to 7% (n = 3) and 0% (n = 0) in the primary tumors (n = 44), respectively. Similar to the observations made by DNA methylation profiling, RNA sequencing of our cohort revealed AT/RT primary tumors and matched recurrences clustering closely together. However, a number of genes showed significantly altered expression in AT/RT-SHH recurrences. Many of them are known tumor driving growth factors, involved in embryonal development and tumorigenesis, or are cell-cycle-associated. Overall, our work identifies subtle molecular changes that occur in the course of the disease and that may help define novel therapeutic targets for AT/RT recurrences., (© 2023. The Author(s).)
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- 2023
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28. The DNA methylation status of the TERT promoter differs between subtypes of mature B-cell lymphomas.
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Kouroukli AG, Fischer A, Kretzmer H, Chteinberg E, Rajaram N, Glaser S, Kolarova J, Bashtrykov P, Mathas S, Drexler HG, Ohno H, Ammerpohl O, Jeltsch A, Siebert R, and Bens S
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- Humans, DNA Methylation, CpG Islands, Lymphoma, B-Cell genetics, Telomerase genetics, Telomerase metabolism
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- 2023
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29. Focal structural variants revealed by whole genome sequencing disrupt the histone demethylase KDM4C in B-cell lymphomas.
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Lopez C, Schleussner N, Bernhart SH, Kleinheinz K, Sungalee S, Sczakiel HL, Kretzmer H, Toprak UH, Glaser S, Wagener R, Ammerpohl O, Bens S, Giefing M, Sanchez JCG, Apic G, Hubschmann D, Janz M, Kreuz M, Mottok A, Muller JM, Seufert J, Hoffmann S, Korbel JO, Russell RB, Schule R, Trumper L, Klapper W, Radlwimmer B, Lichter P, Kuppers R, Schlesner M, Mathas S, and Siebert R
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- Humans, Histones metabolism, Histone Demethylases genetics, Homozygote, Sequence Deletion, Whole Genome Sequencing, RNA, Jumonji Domain-Containing Histone Demethylases genetics, Jumonji Domain-Containing Histone Demethylases chemistry, Jumonji Domain-Containing Histone Demethylases metabolism, Histone-Lysine N-Methyltransferase genetics, Lymphoma genetics, Lymphoma, B-Cell genetics
- Abstract
Histone methylation-modifiers, such as EZH2 and KMT2D, are recurrently altered in B-cell lymphomas. To comprehensively describe the landscape of alterations affecting genes encoding histone methylation-modifiers in lymphomagenesis we investigated whole genome and transcriptome data of 186 mature B-cell lymphomas sequenced in the ICGC MMML-Seq project. Besides confirming common alterations of KMT2D (47% of cases), EZH2 (17%), SETD1B (5%), PRDM9 (4%), KMT2C (4%), and SETD2 (4%), also identified by prior exome or RNA-sequencing studies, we here found recurrent alterations to KDM4C in chromosome 9p24, encoding a histone demethylase. Focal structural variation was the main mechanism of KDM4C alterations, and was independent from 9p24 amplification. We also identified KDM4C alterations in lymphoma cell lines including a focal homozygous deletion in a classical Hodgkin lymphoma cell line. By integrating RNA-sequencing and genome sequencing data we predict that KDM4C structural variants result in loss-offunction. By functional reconstitution studies in cell lines, we provide evidence that KDM4C can act as a tumor suppressor. Thus, we show that identification of structural variants in whole genome sequencing data adds to the comprehensive description of the mutational landscape of lymphomas and, moreover, establish KDM4C as a putative tumor suppressive gene recurrently altered in subsets of B-cell derived lymphomas.
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- 2023
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30. Germline Missense Variants in CDC20 Result in Aberrant Mitotic Progression and Familial Cancer.
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Chen OJ, Castellsagué E, Moustafa-Kamal M, Nadaf J, Rivera B, Fahiminiya S, Wang Y, Gamache I, Pacifico C, Jiang L, Carrot-Zhang J, Witkowski L, Berghuis AM, Schönberger S, Schneider D, Hillmer M, Bens S, Siebert R, Stewart CJR, Zhang Z, Chao WCH, Greenwood CMT, Barford D, Tischkowitz M, Majewski J, Foulkes WD, and Teodoro JG
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- Anaphase-Promoting Complex-Cyclosome genetics, Animals, Cdc20 Proteins genetics, Cdc20 Proteins metabolism, Cell Cycle Proteins genetics, Cell Cycle Proteins metabolism, Germ Cells metabolism, HeLa Cells, Humans, Mice, Mitosis genetics, Protein Binding, Neoplasms metabolism, Spindle Apparatus metabolism
- Abstract
CDC20 is a coactivator of the anaphase promoting complex/cyclosome (APC/C) and is essential for mitotic progression. APC/CCDC20 is inhibited by the spindle assembly checkpoint (SAC), which prevents premature separation of sister chromatids and aneuploidy in daughter cells. Although overexpression of CDC20 is common in many cancers, oncogenic mutations have never been identified in humans. Using whole-exome sequencing, we identified heterozygous missense CDC20 variants (L151R and N331K) that segregate with ovarian germ cell tumors in two families. Functional characterization showed these mutants retain APC/C activation activity but have impaired binding to BUBR1, a component of the SAC. Expression of L151R and N331K variants promoted mitotic slippage in HeLa cells and primary skin fibroblasts derived from carriers. Generation of mice carrying the N331K variant using CRISPR-Cas9 showed that, although homozygous N331K mice were nonviable, heterozygotes displayed accelerated oncogenicity of Myc-driven cancers. These findings highlight an unappreciated role for CDC20 variants as tumor-promoting genes., Significance: Two germline CDC20 missense variants that segregate with cancer in two families compromise the spindle assembly checkpoint and lead to aberrant mitotic progression, which could predispose cells to transformation. See related commentary by Villarroya-Beltri and Malumbres, p. 3432., (©2022 American Association for Cancer Research.)
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- 2022
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31. SMARCB1-deficient and SMARCA4-deficient Malignant Brain Tumors With Complex Copy Number Alterations and TP53 Mutations May Represent the First Clinical Manifestation of Li-Fraumeni Syndrome.
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Hasselblatt M, Thomas C, Federico A, Nemes K, Johann PD, Bison B, Bens S, Dahlum S, Kordes U, Redlich A, Lessel L, Pajtler KW, Mawrin C, Schüller U, Nolte K, Kramm CM, Hinz F, Sahm F, Giannini C, Penkert J, Kratz CP, Pfister SM, Siebert R, Paulus W, Kool M, and Frühwald MC
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- Child, DNA Copy Number Variations, DNA Helicases genetics, DNA Helicases metabolism, Humans, Mutation, Nuclear Proteins genetics, Nuclear Proteins metabolism, SMARCB1 Protein genetics, SMARCB1 Protein metabolism, Transcription Factors genetics, Transcription Factors metabolism, Tumor Suppressor Protein p53 genetics, Brain Neoplasms complications, Brain Neoplasms genetics, Li-Fraumeni Syndrome complications, Li-Fraumeni Syndrome genetics, Rhabdoid Tumor genetics, Rhabdoid Tumor pathology
- Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations of SMARCB1 or (rarely) SMARCA4 causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising from other central nervous system tumors have been reported. Malignant gliomas, IDH wild-type, arising in patients with Li-Fraumeni syndrome typically show somatic mutations of TP53 as well as complex copy number alterations, but little is known about the loss of SMARCB1 or SMARCA4 protein expression in this context. Here, we report 2 children in whom malignant supratentorial brain tumors with SMARCB1 deficiency, complex copy number alterations, and somatic TP53 mutations lead to the discovery of pathogenic/likely pathogenic TP53 variants in the germline. Screening of the molecularneuropathology.org dataset for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4 deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1-deficient or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somatic TP53 mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation for TP53 germline status., Competing Interests: Conflicts of Interest and Source of Funding: Supported by IZKF Münster (Ha3/017/20). C.P.K. has been supported by the Deutsche Kinderkrebsstiftung (DKS2019.13) and BMBF ADDRess (01GM1909A). B.B. is supported by the Deutsche Kinderkrebsstiftung (DKS 2020.05). M.C.F. and R.S. are supported Deutsche Krebshilfe (DKH 70113981, 70114040). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2022
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32. Successful Retreatment With Venetoclax in a Patient With Chronic Lymphocytic Leukemia.
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Jackson RA, Smith VM, Jayne S, Drewes C, Bens S, Siebert R, Dyer MJS, and Walter HS
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- 2022
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33. T-cell prolymphocytic leukemia is associated with deregulation of oncogenic microRNAs on transcriptional and epigenetic level.
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Patil P, Hillebrecht S, Chteinberg E, López C, Toprak UH, Seufert J, Bernhart SH, Kretzmer H, Bergmann AK, Bens S, Högel J, Müller A, Jebaraj BM, Schrader A, Johansson P, Costa D, Schlesner M, Dürig J, Herling M, Campo E, Stilgenbauer S, Wiehle L, and Siebert R
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- Carcinogenesis genetics, DNA Methylation genetics, Epigenesis, Genetic, Humans, Leukemia, Prolymphocytic, T-Cell genetics, MicroRNAs genetics
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Deregulation of micro(mi)-RNAs is a common mechanism in tumorigenesis. We investigated the expression of 2083 miRNAs in T-cell prolymphocytic leukemia (T-PLL). Compared to physiologic CD4+ and CD8+ T-cell subsets, 111 miRNAs were differentially expressed in T-PLL. Of these, 33 belonged to miRNA gene clusters linked to cancer. Genomic variants affecting miRNAs were infrequent with the notable exception of copy number aberrations. Remarkably, we found strong upregulation of the miR-200c/-141 cluster in T-PLL to be associated with DNA hypomethylation and active promoter marks. Our findings suggest that copy number aberrations and epigenetic changes could contribute to miRNA deregulation in T-PLL., (© 2022 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)
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- 2022
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34. ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance.
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Federico A, Thomas C, Miskiewicz K, Woltering N, Zin F, Nemes K, Bison B, Johann PD, Hawes D, Bens S, Kordes U, Albrecht S, Dohmen H, Hauser P, Keyvani K, van Landeghem FKH, Lund EL, Scheie D, Mawrin C, Monoranu CM, Parm Ulhøi B, Pietsch T, Reinhard H, Riemenschneider MJ, Sehested A, Sumerauer D, Siebert R, Paulus W, Frühwald MC, Kool M, and Hasselblatt M
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- DNA Methylation, Hedgehog Proteins genetics, Hedgehog Proteins metabolism, Humans, Prognosis, SMARCB1 Protein genetics, SMARCB1 Protein metabolism, Central Nervous System Neoplasms genetics, Neoplasms, Neuroepithelial genetics, Rhabdoid Tumor genetics, Teratoma genetics
- Abstract
Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest molecular group and is heterogeneous with regard to age, tumor location and epigenetic profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might also have biological and clinical importance. Consensus clustering of DNA methylation profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location (SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial, often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells not only altered hedgehog signaling, but also caused aberrant Notch signaling and formation of tumor-like structures. Finally, on survival analysis, molecular subgroup and age of onset (but not ASCL1 staining status) were independently associated with overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized by SHH and Notch pathway activation, but divergent molecular and clinical features. Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and might aid to stratify patients within future clinical trials., (© 2022. The Author(s).)
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- 2022
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35. Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant: A clinical and histopathological distinct entity showing epigenetic similarity with ATRT-MYC.
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Hasselblatt M, Thomas C, Federico A, Bens S, Hellström M, Casar-Borota O, Kordes U, Neumann JE, Dottermusch M, Rodriguez FJ, Lo AC, Cheng S, Hendson G, Hukin J, Hartmann C, Koch A, Capper D, Siebert R, Paulus W, Nemes K, Johann PD, Frühwald MC, and Kool M
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- Child, Epigenesis, Genetic, Humans, SMARCB1 Protein genetics, Young Adult, Rhabdoid Tumor pathology, Teratoma
- Abstract
Low-grade diffusely infiltrative tumour (LGDIT), SMARCB1-mutant, is a histopathological distinct low-grade lesion encountered in older children and young adults that shows epigenetic similarity with ATRT-MYC and has the potential for malignant progression., (© 2022 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.)
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- 2022
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36. Integration of Maps Enables a Cytogenomics Analysis of the Complete Karyotype in Solea senegalensis .
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Ramírez D, Rodríguez ME, Cross I, Arias-Pérez A, Merlo MA, Anaya M, Portela-Bens S, Martínez P, Robles F, Ruiz-Rejón C, and Rebordinos L
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- Animals, Karyotype, Karyotyping, Synteny genetics, DNA Transposable Elements, Flatfishes genetics
- Abstract
The Pleuronectiformes order, which includes several commercially-important species, has undergone extensive chromosome evolution. One of these species is Solea senegalensis , a flatfish with 2 n = 42 chromosomes. In this study, a cytogenomics approach and integration with previous maps was applied to characterize the karyotype of the species. Synteny analysis of S. senegalensis was carried out using two flatfish as a reference: Cynoglossus semilaevis and Scophthalmus maximus . Most S. senegalensis chromosomes (or chromosome arms for metacentrics and submetacentrics) showed a one-to-one macrosyntenic pattern with the other two species. In addition, we studied how repetitive sequences could have played a role in the evolution of S. senegalensis bi-armed (3, and 5-9) and acrocentric (11, 12 and 16) chromosomes, which showed the highest rearrangements compared with the reference species. A higher abundance of TEs (Transposable Elements) and other repeated elements was observed adjacent to telomeric regions on chromosomes 3, 7, 9 and 16. However, on chromosome 11, a greater abundance of DNA transposons was detected in interstitial BACs. This chromosome is syntenic with several chromosomes of the other two flatfish species, suggesting rearrangements during its evolution. A similar situation was also found on chromosome 16 (for microsatellites and low complexity sequences), but not for TEs (retroelements and DNA transposons). These differences in the distribution and abundance of repetitive elements in chromosomes that have undergone remodeling processes during the course of evolution also suggest a possible role for simple repeat sequences in rearranged regions.
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- 2022
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37. Infants and Newborns with Atypical Teratoid Rhabdoid Tumors (ATRT) and Extracranial Malignant Rhabdoid Tumors (eMRT) in the EU-RHAB Registry: A Unique and Challenging Population.
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Nemes K, Johann PD, Steinbügl M, Gruhle M, Bens S, Kachanov D, Teleshova M, Hauser P, Simon T, Tippelt S, Eberl W, Chada M, Lopez VS, Grigull L, Hernáiz-Driever P, Eyrich M, Pears J, Milde T, Reinhard H, Leipold A, van de Wetering M, Gil-da-Costa MJ, Ebetsberger-Dachs G, Kerl K, Lemmer A, Boztug H, Furtwängler R, Kordes U, Vokuhl C, Hasselblatt M, Bison B, Kröncke T, Melchior P, Timmermann B, Gerss J, Siebert R, and Frühwald MC
- Abstract
Introduction: Malignant rhabdoid tumors (MRT) predominantly affect infants and young children. Patients below six months of age represent a particularly therapeutically challenging group. Toxicity to developing organ sites limits intensity of treatment. Information on prognostic factors, genetics, toxicity of treatment and long-term outcomes is sparse. Methods: Clinical, genetic, and treatment data of 100 patients (aged below 6 months at diagnosis) from 13 European countries were analyzed (2005-2020). Tumors and matching blood samples were examined for SMARCB1 mutations using FISH, MLPA and Sanger sequencing. DNA methylation subgroups (ATRT-TYR, ATRT-SHH, and ATRT-MYC) were determined using 450 k / 850 k-profiling. Results: A total of 45 patients presented with ATRT, 29 with extracranial, extrarenal (eMRT) and 9 with renal rhabdoid tumors (RTK). Seventeen patients demonstrated synchronous tumors (SYN). Metastases (M+) were present in 27% (26/97) at diagnosis. A germline mutation (GLM) was detected in 55% (47/86). DNA methylation subgrouping was available in 50% (31 / 62) with ATRT or SYN; for eMRT, methylation-based subgrouping was not performed. The 5-year overall (OS) and event free survival (EFS) rates were 23.5 ± 4.6% and 19 ± 4.1%, respectively. Male sex (11 ± 5% vs. 35.8 ± 7.4%), M+ stage (6.1 ± 5.4% vs. 36.2 ± 7.4%), presence of SYN (7.1 ± 6.9% vs. 26.6 ± 5.3%) and GLM (7.7 ± 4.2% vs. 45.7 ± 8.6%) were significant prognostic factors for 5-year OS. Molecular subgrouping and survival analyses confirm a previously described survival advantage for ATRT-TYR. In an adjusted multivariate model, clinical factors that favorably influence the prognosis were female sex, localized stage, absence of a GLM and maintenance therapy. Conclusions: In this cohort of homogenously treated infants with MRT, significant predictors of outcome were sex, M-stage, GLM and maintenance therapy. We confirm the need to stratify which patient groups benefit from multimodal treatment, and which need novel therapeutic strategies. Biomarker-driven tailored trials may be a key option.
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- 2022
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38. CDKN2A -Mutated Pancreatic Ductal Organoids from Induced Pluripotent Stem Cells to Model a Cancer Predisposition Syndrome.
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Merkle J, Breunig M, Schmid M, Allgöwer C, Krüger J, Melzer MK, Bens S, Siebert R, Perkhofer L, Azoitei N, Seufferlein T, Heller S, Meier M, Müller M, Kleger A, and Hohwieler M
- Abstract
Patient-derived induced pluripotent stem cells (iPSCs) provide a unique platform to study hereditary disorders and predisposition syndromes by resembling germline mutations of affected individuals and by their potential to differentiate into nearly every cell type of the human body. We employed plucked human hair from two siblings with a family history of cancer carrying a pathogenic CDKN2A variant, P16-p.G101W/P14-p.R115L, to generate patient-specific iPSCs in a cancer-prone ancestry for downstream analytics. The differentiation capacity to pancreatic progenitors and to pancreatic duct-like organoids (PDLOs) according to a recently developed protocol remained unaffected. Upon inducible expression of KRAS
G12D using a piggyBac transposon system in CDKN2A-mutated PDLOs, we revealed structural and molecular changes in vitro, including disturbed polarity and epithelial-to-mesenchymal (EMT) transition. CDKN2A -mutated KRASG12D PDLO xenotransplants formed either a high-grade precancer lesion or a partially dedifferentiated PDAC-like tumor. Intriguingly, P14/P53/P21 and P16/RB cell-cycle checkpoint controls have been only partly overcome in these grafts, thereby still restricting the tumorous growth. Hereby, we provide a model for hereditary human pancreatic cancer that enables dissection of tumor initiation and early development starting from patient-specific CDKN2A -mutated pluripotent stem cells.- Published
- 2021
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39. Molecular characterization of Burkitt lymphoma in the breast or ovary.
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Elgaafary S, López C, Nagel I, Vater I, Bens S, Szczepanowski M, Aukema SM, Wagener R, Hopp L, Binder H, de Leval L, Klapper W, and Siebert R
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- Female, Humans, In Situ Hybridization, Fluorescence, Ovary, Translocation, Genetic, Burkitt Lymphoma diagnosis, Burkitt Lymphoma genetics, Lymphoma genetics, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
Breast and ovary have been described as rare but typical sites of presentation of Burkitt lymphoma (BL) in females, particularly after puberty. We revised a historic series of 44 lymphomas of the breast or the ovary in women diagnosed between 1973 and 2014 as BL. Fluorescence in situ hybridization (FISH) was applied to all, and array-based copy number analysis as well as expression profiling to a subset of those cases. Of the 42 cases evaluable for FISH, 19 cases showed an IG- MYC translocation but only 9 of those fulfilled the criteria of the current WHO classification for the diagnosis of BL. Those nine cases resembled BL of other sites with regard to molecular features. Our findings along with literature data suggest that breast and ovarian BL (1) seem to be rarer than hitherto assumed, (2) share typical molecular features with other BL, and (3) predominantly affect women in the fertile age.
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- 2021
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40. Atypical Teratoid/Rhabdoid Tumor (AT/RT) With Molecular Features of Pleomorphic Xanthoastrocytoma.
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Thomas C, Federico A, Sill M, Bens S, Oyen F, Nemes K, Johann PD, Hartmann C, Hartmann W, Sumerauer D, Paterno V, Samii A, Kordes U, Siebert R, Frühwald MC, Paulus W, Kool M, and Hasselblatt M
- Subjects
- Adolescent, Child, Female, Humans, Mutation, Proto-Oncogene Proteins B-raf genetics, SMARCB1 Protein genetics, Astrocytoma genetics, Brain Neoplasms genetics, Rhabdoid Tumor genetics, Teratoma genetics
- Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant central nervous system tumor predominantly occurring in infants that may also arise in older children and adults. Rare secondary AT/RT developing from other tumors such as pleomorphic xanthoastrocytoma (PXA) are on record, but AT/RT presenting with molecular features of PXA have not been described. Here, we report 3 malignant central nervous system tumors in children (10, 13, and 18 y old). All tumors were located in the temporal lobe. In 2 cases, there was no history of a low-grade precursor lesion; in 1 case anaplastic PXA had been diagnosed 3 months earlier. Histopathologically, all tumors were composed of RT cells and showed frank signs of malignancy as well as loss of nuclear SMARCB1/INI1 protein expression. Two cases displayed homozygous deletions of the SMARCB1 region while the third case showed an exon 7 mutation (c.849_850delGT; p.Met283Ilefs*77). Of note, DNA methylation profiles did not group with AT/RT or other tumor entities using the Heidelberg Brain Tumor Classifier (version v11b4). By unsupervised t-distributed stochastic neighbor embedding analysis and hierarchical clustering analysis, however, all tumors clearly grouped with PXA. Genome-wide copy number analysis revealed homozygous CDNK2A/B deletions and gains of whole chromosome 7. BRAF V600E mutations could be demonstrated in all cases. In conclusion, the possibility of AT/RT with molecular features of PXA needs to be taken into account and warrants molecular characterization of AT/RT especially in older children. Since treatments targeting mutated BRAF are available, identification of such cases may also have therapeutic consequences., Competing Interests: Conflicts of Interest and Source of Funding: M.H. and C.T. are supported by Deutsche Forschungsgemeinschaft (HA 3060/8-1 and TH 2345/1-1). The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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41. Transposable element insertion as a mechanism of SMARCB1 inactivation in atypical teratoid/rhabdoid tumor.
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Thomas C, Oehl-Huber K, Bens S, Soschinski P, Koch A, Nemes K, Oyen F, Kordes U, Kool M, Frühwald MC, Hasselblatt M, and Siebert R
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- Brain Neoplasms pathology, DNA Transposable Elements, Female, Humans, Infant, Mutagenesis, Insertional, Rhabdoid Tumor pathology, Teratoma pathology, Brain Neoplasms genetics, Rhabdoid Tumor genetics, SMARCB1 Protein genetics, Teratoma genetics
- Abstract
Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant brain tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which may be also present in the germline (rhabdoid tumor predisposition syndrome 1), as well as somatic copy-number neutral loss of heterozygosity (LOH). In some SMARCB1-deficient AT/RT underlying biallelic mutations cannot be identified. Here we report the case of a 24-months-old girl diagnosed with a large brain tumor. The malignant rhabdoid tumor showed loss of nuclear SMARCB1/INI1 protein expression and the diagnosis of AT/RT was confirmed by DNA methylation profiling. While FISH, MLPA, Sanger sequencing and DNA methylation data-based imbalance analysis did not disclose alterations affecting SMARCB1, OncoScan array analysis revealed a 28.29 Mb sized region of copy-number neutral LOH on chromosome 22q involving the SMARCB1 locus. Targeted next-generation sequencing did also not detect a single nucleotide variant but instead revealed insertion of an AluY element into exon 2 of SMARCB1. Specific PCR-based Sanger sequencing verified the Alu insertion (SMARCB1 c.199_200 Alu ins) resulting in a frame-shift truncation not present in the patient's germline. In conclusion, transposable element insertion represents a hitherto not widely recognized mechanism of SMARCB1 disruption in AT/RT, which might not be detected by several widely applied conventional diagnostics assays. This finding has particular clinical implications, if rhabdoid predisposition syndrome 1 is suspected, but germline SMARCB1 alterations cannot be identified., (© 2021 The Authors. Genes, Chromosomes and Cancer published by Wiley Periodicals LLC.)
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- 2021
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42. Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.
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Pathak R, Zin F, Thomas C, Bens S, Gayden T, Karamchandani J, Dudley RW, Nemes K, Johann PD, Oyen F, Kordes U, Jabado N, Siebert R, Paulus W, Kool M, Frühwald MC, Albrecht S, Kalpana GV, and Hasselblatt M
- Subjects
- Central Nervous System Neoplasms genetics, Central Nervous System Neoplasms metabolism, Child, Preschool, Female, Genes, Tumor Suppressor physiology, Humans, Infant, Male, Mutation genetics, Neoplasm, Residual metabolism, Neoplasms, Neuroepithelial genetics, Neoplasms, Neuroepithelial metabolism, Rhabdoid Tumor genetics, SMARCB1 Protein genetics, Teratoma genetics, Active Transport, Cell Nucleus physiology, Neoplasm, Residual genetics, Rhabdoid Tumor metabolism, SMARCB1 Protein metabolism
- Abstract
Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated β-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations., (© 2021. The Author(s).)
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- 2021
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43. Mantle cell lymphomas with concomitant MYC and CCND1 breakpoints are recurrently TdT positive and frequently show high-grade pathological and genetic features.
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Aukema SM, Croci GA, Bens S, Oehl-Huber K, Wagener R, Ott G, Rosenwald A, Kluin PM, van den Berg E, Bosga-Bouwer AG, Hoogendoorn M, Hoster E, Bittmann I, Nagel I, Murga Penas EM, Kreuz M, Bausinger J, Belder W, Oschlies I, Dyer MJS, Jayne S, Siebert R, and Klapper W
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Tumor analysis, Child, Preschool, Clonal Evolution, Comparative Genomic Hybridization, Cytogenetic Analysis, DNA Nucleotidylexotransferase analysis, Diagnosis, Differential, Female, Genetic Predisposition to Disease, Humans, Immunohistochemistry, Immunophenotyping, Lymphoma, Mantle-Cell immunology, Lymphoma, Mantle-Cell pathology, Male, Middle Aged, Neoplasm Grading, Phenotype, Predictive Value of Tests, Biomarkers, Tumor genetics, Chromosome Breakpoints, Cyclin D1 genetics, Gene Rearrangement, Lymphoma, Mantle-Cell genetics, Proto-Oncogene Proteins c-myc genetics
- Abstract
Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)
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- 2021
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44. Desmoplastic myxoid tumor of pineal region, SMARCB1-mutant, in young adult.
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Manoranjan B, Starreveld YP, Nordal RA, Dunham C, Bens S, Thomas C, Hasselblatt M, and Joseph JT
- Abstract
We present a young adult woman who developed a myxoid tumor of the pineal region having a SMARCB1 mutation, which was phenotypically similar to the recently described desmoplastic myxoid, SMARCB1 -mutant tumor of the pineal region (DMT-SMARCB1). The 24-year-old woman presented with headaches, nausea, and emesis. Neuroimaging identified a hypodense lesion in CT scans that was T
1 -hypointense, hyperintense in both T2 -weighted and FLAIR MRI scans, and displayed gadolinium enhancement. The resected tumor had an abundant, Alcian-blue positive myxoid matrix with interspersed, non-neoplastic neuropil-glial-vascular elements. It immunoreacted with CD34 and individual cells for EMA. Immunohistochemistry revealed loss of nuclear INI1 expression by the myxoid component but its retention in the vascular elements. Molecular analyses identified a SMARCB1 deletion and DNA methylation studies showed that this tumor grouped together with the recently described DMT-SMARCB1. A cerebrospinal fluid cytologic preparation had several cells morphologically similar to those in routine and electron microscopy. We briefly discuss the correlation of the pathology with the radiology and how this tumor compares with other SMARCB1 -mutant tumors of the nervous system.- Published
- 2021
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45. A Diagnostic Approach to the Identification of Burkitt-like Lymphoma With 11q Aberration in Aggressive B-Cell Lymphomas.
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Horn H, Kalmbach S, Wagener R, Staiger AM, Hüttl K, Mottok A, Bens S, Traverse-Glehen A, Fontaine J, Siebert R, Rosenwald A, and Ott G
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- Apoptosis, Burkitt Lymphoma classification, Burkitt Lymphoma pathology, Genetic Predisposition to Disease, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse classification, Lymphoma, Large B-Cell, Diffuse pathology, Neoplasm Grading, Phenotype, Predictive Value of Tests, Retrospective Studies, Terminology as Topic, Tumor-Associated Macrophages, Burkitt Lymphoma genetics, Chromosome Aberrations, Chromosomes, Human, Pair 11, Lymphoma, Large B-Cell, Diffuse genetics, Molecular Diagnostic Techniques
- Abstract
Rare cases of aggressive B-cell lymphomas with a morphology similar to Burkitt lymphoma (BL) present with the BL-typical immunophenotype, but lacked MYC translocation (MYC-negative Burkitt-like lymphoma: mnBLL). A proportion of those with an imbalance pattern in chromosome 11q has been designated Burkitt-like lymphoma with 11q aberration in the recent update of the World Health Organization (WHO) classification. Because of the problems in the identification of Burkitt-like lymphoma with 11q aberration, our goal was to retrospectively analyze their frequency in a cohort of "candidate" aggressive lymphomas (cohort 1, n=35) such as mnBLL (n=16), diffuse large B-cell lymphoma with similarities to Burkitt lymphoma (DLBCL-BL; n=3), high-grade B-cell lymphomas, not otherwise specified (NOS) (n=16), as well as in a cohort of MYC-negative diffuse large B-cell lymphoma NOS (cohort 2, n=62). In total, 17/33 cohort 1 cases (52%) harbored the typical 11q aberration pattern, predominantly those that had been classified as mnBLL (12/16, 75%), but also as DLBCL-BL (2/3, 67%) and high-grade B-cell lymphomas, NOS (3/14; 21%). The specimens with this typical 11q aberration pattern were usually negative for the BCL2 protein. Of interest and as a new finding, samples harboring the 11q aberration pattern were often characterized by strikingly coarse apoptotic debris within starry sky macrophages facilitating their recognition. In contrast, only 1 of 62 garden variety DLBCL, NOS was positive for the 11q aberration pattern. In 2 DLBCL-BL, a dual MYC translocation/11q aberration pattern was detected. As a diagnostic algorithm, we, therefore, propose analysis of 11q status in MYC-negative high-grade lymphomas with features of BL, especially showing BCL2 negativity and a conspicuous coarse apoptotic debris in starry sky macrophages., Competing Interests: Conflicts of Interest and Source of Funding: Supported by the German José Carreras Leukämie-Stiftung (DJCLS R 10/28) and the Robert Bosch-Stiftung (Project O3), Stuttgart, Germany. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)
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- 2021
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46. Cytogenomics Unveil Possible Transposable Elements Driving Rearrangements in Chromosomes 2 and 4 of Solea senegalensis .
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Rodríguez ME, Cross I, Arias-Pérez A, Portela-Bens S, Merlo MA, Liehr T, and Rebordinos L
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- Animals, Chromosome Aberrations, Chromosome Mapping, Chromosomes, Artificial, Bacterial genetics, Evolution, Molecular, In Situ Hybridization, Fluorescence, Karyotype, Phylogeny, Synteny, Chromosomes genetics, Cytogenetics methods, DNA Transposable Elements, Flatfishes genetics
- Abstract
Cytogenomics, the integration of cytogenetic and genomic data, has been used here to reconstruct the evolution of chromosomes 2 and 4 of Solea senegalensis . S. senegalensis is a flat fish with a karyotype comprising 2n = 42 chromosomes: 6 metacentric + 4 submetacentric + 8 subtelocentric + 24 telocentric. The Fluorescence in situ Hybridization with Bacterial Artificial Chromosomes (FISH-BAC) technique was applied to locate BACs in these chromosomes (11 and 10 BACs in chromosomes 2 and 4, respectively) and to generate integrated maps. Synteny analysis, taking eight reference fish species ( Cynoglossus semilaevis , Scophthalmus maximus , Sparus aurata , Gasterosteus aculeatus , Xiphophorus maculatus , Oryzias latipes , Danio rerio, and Lepisosteus oculatus ) for comparison, showed that the BACs of these two chromosomes of S. senegalensis were mainly distributed in two principal chromosomes in the reference species. Transposable Elements (TE) analysis showed significant differences between the two chromosomes, in terms of number of loci per Mb and coverage, and the class of TE (I or II) present. Analysis of TE divergence in chromosomes 2 and 4 compared to their syntenic regions in four reference fish species ( C. semilaevis , S. maximus , O. latipes, and D. rerio ) revealed differences in their age of activity compared with those species but less notable differences between the two chromosomes. Differences were also observed in peaks of divergence and coverage of TE families for all reference species even in those close to S. senegalensis, like S. maximus and C. semilaevis . Considered together, chromosomes 2 and 4 have evolved by Robertsonian fusions, pericentric inversions, and other chromosomal rearrangements mediated by TEs.
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- 2021
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47. Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).
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Nemes K, Bens S, Kachanov D, Teleshova M, Hauser P, Simon T, Tippelt S, Woessmann W, Beck O, Flotho C, Grigull L, Driever PH, Schlegel PG, Khurana C, Hering K, Kolb R, Leipold A, Abbink F, Gil-Da-Costa MJ, Benesch M, Kerl K, Lowis S, Marques CH, Graf N, Nysom K, Vokuhl C, Melchior P, Kröncke T, Schneppenheim R, Kordes U, Gerss J, Siebert R, Furtwängler R, and Frühwald MC
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- Adolescent, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Risk Factors, Rhabdoid Tumor epidemiology
- Abstract
Introduction: Extracranial rhabdoid tumours are rare, highly aggressive malignancies primarily affecting young children. The EU-RHAB registry was initiated in 2009 to prospectively collect data of rhabdoid tumour patients treated according to the EU-RHAB therapeutic framework., Methods: We evaluated 100 patients recruited within EU-RHAB (2009-2018). Tumours and matching blood samples were examined for SMARCB1 mutations by sequencing and cytogenetics., Results: A total of 70 patients presented with extracranial, extrarenal tumours (eMRT) and 30 with renal rhabdoid tumours (RTK). Nine patients demonstrated synchronous tumours. Distant metastases at diagnosis (M+) were present in 35% (35/100), localised disease (M0) with (LN+) and without (LN-) loco-regional lymph node involvement in 65% (65/100). SMARCB1 germline mutations (GLM) were detected in 21% (17/81 evaluable) of patients. The 5-year overall survival (OS) and event-free survival (EFS) rates were 45.8 ± 5.4% and 35.2 ± 5.1%, respectively. On univariate analyses, age at diagnosis (≥12 months), M0-stage, absence of synchronous tumours, absence of a GLM, gross total resection (GTR), radiotherapy and achieving a CR were significantly associated with favourable outcomes. In an adjusted multivariate model presence of a GLM, M+ and lack of a GTR were the strongest significant negative predictors of outcome., Conclusions: We suggest to stratify patients with localised disease (M0), GTR+ and without proof of a GLM (5-year OS 72.2 ± 9.9%) as 'standard risk'. Patients presenting with one of the features M+ and/or GTR- and/or GLM+ belong to a high risk group (5-year, OS 32.5 ± 6.2%). These patients need novel therapeutic strategies such as combinations of targeted agents with conventional chemotherapy or novel experimental approaches ideally within international phase I/II trials., Competing Interests: Conflict of interest statement We hereby confirm, that there are no conflict of interest disclosures from any authors. Pablo Hernáiz Driever has received travel grants from Novartis. Reiner Siebert has received speaker's honoraries from Astra Zeneca und Roche. None of the other authors declare any conflict of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)
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- 2021
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48. A Comprehensive Integrated Genetic Map of the Complete Karyotype of Solea senegalensis (Kaup 1858).
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Merlo MA, Portela-Bens S, Rodríguez ME, García-Angulo A, Cross I, Arias-Pérez A, García E, and Rebordinos L
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- Animals, Aquaculture methods, Biological Evolution, Chromosomes, Artificial, Bacterial, Cytogenetic Analysis, Fish Proteins classification, Flatfishes classification, Gene Ontology, Molecular Sequence Annotation, Phylogeny, Chromosome Mapping methods, Fish Proteins genetics, Flatfishes genetics, Genome
- Abstract
Solea senegalensis aquaculture production has experienced a great increase in the last decade and, consequently, the genome knowledge of the species is gaining attention. In this sense, obtaining a high-density genome mapping of the species could offer clues to the aquaculture improvement in those aspects not resolved so far. In the present article, a review and new processed data have allowed to obtain a high-density BAC-based cytogenetic map of S. senegalensis beside the analysis of the sequences of such BAC clones to achieve integrative data. A total of 93 BAC clones were used to localize the chromosome complement of the species and 588 genes were annotated, thus almost reaching the 2.5% of the S. senegalensis genome sequences. As a result, important data about its genome organization and evolution were obtained, such as the lesser gene density of the large metacentric pair compared with the other metacentric chromosomes, which supports the theory of a sex proto-chromosome pair. In addition, chromosomes with a high number of linked genes that are conserved, even in distant species, were detected. This kind of result widens the knowledge of this species' chromosome dynamics and evolution.
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- 2020
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49. Double-hit lymphoma of the male breast: a case report.
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Elgaafary S, Nagel I, López C, Bens S, Szczepanowski M, Wagener R, Klapper W, and Siebert R
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- Aged, Female, Humans, In Situ Hybridization, Fluorescence, Male, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-myc genetics, Translocation, Genetic, Burkitt Lymphoma diagnosis, Burkitt Lymphoma drug therapy, Burkitt Lymphoma genetics, Lymphoma, B-Cell diagnosis, Lymphoma, B-Cell genetics
- Abstract
Background: Whereas lymphoma of the female breast is already rare, lymphoma of the male breast has only anecdotally been reported. Within a study of 32 lymphoma of the breast reported between 1973 and 2014 as Burkitt lymphoma, we observed a single male case, which we report here., Case Presentation: A 72-years-old Caucasian man presented with a mass in his left breast. Clinical history included prior basal cell carcinoma, leiomyosarcoma, and administration of spironolactone. The reference pathology diagnosis at presentation was Burkitt lymphoma according to the Kiel Classification. The present re-investigation using fluorescence in situ hybridization revealed an IGH-MYC translocation and a break in the BCL2 locus in the tumor cells. Thus, in light of the current WHO classification, the diagnosis was revised to high-grade B-cell lymphoma with MYC and BCL2 rearrangement, Burkitt morphology (so-called "double-hit" lymphoma). Genome-wide chromosomal imbalance mapping revealed a complex pattern of aberrations in line with this diagnosis. The aberrations, including copy-number gains in chromosomes 3q and 18 and focal homozygous loss in 9p21.3, resembled typical changes of lymphomas affecting "immune-privileged" sites., Conclusion: The present case adds to the understanding of the pathogenesis of male breast lymphomas, about which hardly any molecular characterization has been published yet.
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- 2020
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50. The genomic structure of the highly-conserved dmrt1 gene in Solea senegalensis (Kaup, 1868) shows an unexpected intragenic duplication.
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Cross I, García E, Rodríguez ME, Arias-Pérez A, Portela-Bens S, Merlo MA, and Rebordinos L
- Subjects
- Alternative Splicing genetics, Amino Acid Sequence, Animals, Base Sequence, DNA, Complementary genetics, Exons genetics, Gene Library, Gene Regulatory Networks, Genetic Variation, Phylogeny, Repetitive Sequences, Nucleic Acid genetics, Transcription Factors chemistry, Conserved Sequence genetics, Flatfishes genetics, Gene Duplication, Genome, Transcription Factors genetics
- Abstract
Knowing the factors responsible for sex determination in a species has significant theoretical and practical implications; the dmrt1 gene (Doublesex and Mab-3 (DM)-related Transcription factor 1) plays this role in diverse animal species. Solea senegalensis is a commercially important flat fish in which females grow 30% faster than males. It has 2n = 42 chromosomes and an XX / XY chromosome system for sex determination, without heteromorph chromosomes but with sex proto-chromosome. In the present study, we are providing the genomic structure and nucleotide sequence of dmrt1 gene obtained from cDNA from male and female adult gonads. A cDNA of 2027 containing an open-reading frame (ORF) of 1206 bp and encoding a 402 aa protein it is described for dmrt1 gene of S. senegalensis. Multiple mRNA isoforms indicating a high variable system of alternative splicing in the expression of dmrt1 of the sole in gonads were studied. None isoforms could be related to sex of individuals. The genomic structure of the dmrt1 of S. senegalensis showed a gene of 31400 bp composed of 7 exons and 6 introns. It contains an unexpected duplication of more than 10399 bp, involving part of the exon I, exons II and III and a SINE element found in the sequence that it is proposed as responsible for the duplication. A mature miRNA of 21 bp in length was localized at 336 bp from exon V. Protein-protein interacting networks of the dmrt1 gene showed matches with dmrt1 protein from Cynoglossus semilaevis and a protein interaction network with 11 nodes (dmrt1 plus 10 other proteins). The phylogenetic relationship of the dmrt1 gene in S. senegalensis is consistent with the evolutionary position of its species. The molecular characterization of this gene will enhance its functional analysis and the understanding of sex differentiation in Solea senegalensis and other flatfish., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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