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Sylvia Hartmann,
Stefan Gesk,
René Scholtysik,
Markus Kreuz, Stefanie Bug,
Inga Vater,
Claudia Döring,
Sergio Cogliatti,
Marie Parrens,
Jean-Philippe Merlio,
Anna Kwiecinska,
Anna Porwit,
Pier Paolo Piccaluga,
Stefano Pileri,
Gerald Hoefler,
Ralf Küppers,
Reiner Siebert,
Martin-Leo Hansmann
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ABSTRACT: Little is known about genomic aberrations in peripheral T cell lymphoma, not otherwise specified (PTCL NOS). We studied 47 PTCL NOS by 250k GeneChip single nucleotide polymorphism arrays and detected genomic imbalances in 22 of the cases. Recurrent gains and losses were identified, including gains of chromosome regions 1q32-43, 2p15-16, 7, 8q24, 11q14-25, 17q11-21 and 21q11-21 (> or = 5 cases each) as well as losses of chromosome regions 1p35-36, 5q33, 6p22, 6q16, 6q21-22, 8p21-23, 9p21, 10p11-12, 10q11-22, 10q25-26, 13q14, 15q24, 16q22, 16q24, 17p11, 17p13 and Xp22 (> or = 4 cases each). Genomic imbalances affected several regions containing members of nuclear factor-kappaB signalling and genes involved in cell cycle control. Gains of 2p15-16 were confirmed in each of three cases analysed by fluorescence in situ hybridization (FISH) and were associated with breakpoints at the REL locus in two of these cases. Three additional cases with gains of the REL locus were detected by FISH among 18 further PTCL NOS. Five of 27 PTCL NOS investigated showed nuclear expression of the REL protein by immunohistochemistry, partly associated with genomic gains of the REL locus. Therefore, in a subgroup of PTCL NOS gains/rearrangements of REL and expression of REL protein may be of pathogenetic relevance.
British Journal of Haematology 10/2009; 148(3):402-12. · 4.94 Impact Factor
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Stefanie Bug,
Jan Dürig,
Florian Oyen,
Ludger Klein-Hitpass,
Jose I Martin-Subero,
Lana Harder,
Michael Baudis,
Norbert Arnold,
Uwe Kordes,
Ulrich Dührsen,
Reinhard Schneppenheim,
Reiner Siebert
[show abstract]
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ABSTRACT: In T-cell prolymphocytic leukemia (T-PLL), chromosomal imbalances affecting the long arm of chromosome 22 are regarded as typical chromosomal aberrations secondary to a TCRAD-TCL1A fusion due to inv(14) or t(14;14). We analyzed recently obtained data from conventional karyotyping, SNP-chip array copy number mapping, genome-wide expression profiling, and interphase fluorescence in situ hybridization (FISH) of inv(14)-positive T-PLL with respect to structural aberrations on chromosome 22. Combined gene chip and interphase FISH analyses revealed interstitial deletions on 22q in 4 of 12 cases, with one case additionally showing a terminal copy number gain. A minimally deleted region of approximately 9.1 Mb was delineated, from 16.2 Mb (22cen) to 25.3 Mb (22q12.1). The distal borders of copy number alterations spread over a region of approximately 8.8 Mb, from 25.2 Mb (22q12.1) to 34 Mb (22q12.3). Mutation screening of candidate tumor suppressor genes SMARCB1 and CHEK2 mapping to the minimally deleted and the breakpoint regions, respectively, in cases with hemizygous deletion, revealed no inactivating mutations. With gene expression profiling, no significantly downregulated genes were identified in the minimally deleted region. We therefore assume that haploinsufficiency or alternative pathomechanisms underlie chromosome 22 aberrations in T-PLL.
Cancer genetics and cytogenetics 08/2009; 192(1):44-7. · 1.54 Impact Factor
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Jose I Martin-Subero,
Ole Ammerpohl,
Marina Bibikova,
Eliza Wickham-Garcia,
Xabier Agirre,
Sara Alvarez,
Monika Brüggemann, Stefanie Bug,
Maria J Calasanz,
Martina Deckert, [......],
José Román-Gómez,
Marc Seifert,
Harald Stein,
Javier Suela,
Lorenz Trümper,
Inga Vater,
Felipe Prosper,
Claudia Haferlach,
Juan Cruz Cigudosa,
Reiner Siebert
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ABSTRACT: Alterations in the DNA methylation pattern are a hallmark of leukemias and lymphomas. However, most epigenetic studies in hematologic neoplasms (HNs) have focused either on the analysis of few candidate genes or many genes and few HN entities, and comprehensive studies are required.
Here, we report for the first time a microarray-based DNA methylation study of 767 genes in 367 HNs diagnosed with 16 of the most representative B-cell (n = 203), T-cell (n = 30), and myeloid (n = 134) neoplasias, as well as 37 samples from different cell types of the hematopoietic system. Using appropriate controls of B-, T-, or myeloid cellular origin, we identified a total of 220 genes hypermethylated in at least one HN entity. In general, promoter hypermethylation was more frequent in lymphoid malignancies than in myeloid malignancies, being germinal center mature B-cell lymphomas as well as B and T precursor lymphoid neoplasias those entities with highest frequency of gene-associated DNA hypermethylation. We also observed a significant correlation between the number of hypermethylated and hypomethylated genes in several mature B-cell neoplasias, but not in precursor B- and T-cell leukemias. Most of the genes becoming hypermethylated contained promoters with high CpG content, and a significant fraction of them are targets of the polycomb repressor complex. Interestingly, T-cell prolymphocytic leukemias show low levels of DNA hypermethylation and a comparatively large number of hypomethylated genes, many of them showing an increased gene expression.
We have characterized the DNA methylation profile of a wide range of different HNs entities. As well as identifying genes showing aberrant DNA methylation in certain HN subtypes, we also detected six genes--DBC1, DIO3, FZD9, HS3ST2, MOS, and MYOD1--that were significantly hypermethylated in B-cell, T-cell, and myeloid malignancies. These might therefore play an important role in the development of different HNs.
PLoS ONE 01/2009; 4(9):e6986. · 4.09 Impact Factor
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Maciej Giefing,
Joachim Arnemann,
Jose Ignacio Martin-Subero,
Inga Nieländer, Stefanie Bug,
Sylvia Hartmann,
Norbert Arnold,
Enrico Tiacci,
Matthias Frank,
Martin-Leo Hansmann,
Ralf Küppers,
Reiner Siebert
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ABSTRACT: Several tumour suppressor genes (TSG) have been identified as a result of mapping homozygous deletions in cancer cells. To identify putative TSG involved in the pathogenesis of classical Hodgkin lymphoma (cHL), we investigated four cHL cell lines (L428, HDLM2, KMH2, L1236) using four different array-Comparative Genomic Hybridisation (array-CGH) platforms and focused on high resolution identification of homozygous deletions. Out of 79 candidate regions of bi-allelic loss identified by array-CGH, besides previously described regions, 28 novel regions of homozygous deletions could be verified by polymerase chain reaction. These regions ranged from 13 kb to 619 kb in size. Eleven of the 28 novel bi-allelic losses were putative copy number polymorphisms. This left 17 regions that might harbour novel tumour suppressors involved in Hodgkin lymphoma. Expression profiling with two different platforms confirmed lack of expression of the majority of the genes located in the homozygous deletions. Furthermore, analysis of ontology annotations of genes located in the homozygously deleted regions indicated an enrichment of genes involved in apoptosis and cell death. In summary, through the mapping of homozygous deletions in cell lines this study identified a series of genes, such as SEPT9, GNG7 and CYBB, which might encode candidate tumour suppressors involved in the pathogenesis of cHL.
British Journal of Haematology 08/2008; 142(6):916-24. · 4.94 Impact Factor
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Cornelius Courts,
Manuel Montesinos-Rongen,
Anna Brunn, Stefanie Bug,
Dörte Siemer,
Volkmar Hans,
Ingmar Blümcke,
Wolfram Klapper,
Carlo Schaller,
Otmar D Wiestler,
Ralf Küppers,
Reiner Siebert,
Martina Deckert
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ABSTRACT: Primary lymphomas of the CNS (PCNSLs) show molecular features of the late germinal center exit B-cell phenotype and are impaired in their terminal differentiation as indicated by a lack of immunoglobulin class switching. Because the positive regulatory domain I protein with ZNF domain (PRDM1/BLIMP1) is a master regulator of terminal B-cell differentiation into plasma cells, we investigated a series of 21 PCNSLs for the presence of mutations in the PRDM1 gene and alterations in the expression pattern of the PRDM1 protein. Direct sequencing of all coding exons of the PRDM1 gene identified deleterious mutations associated with abrogation of PRDM1 protein expression in 4 of 21 (19%) PCNSLs. Thus, similar to systemic diffuse large B-cell lymphomas, PRDM1 may be a tumor suppressor in some PCNSL and contribute to lymphomagenesis by impairing terminal differentiation.
Journal of Neuropathology and Experimental Neurology 07/2008; 67(7):720-7. · 4.26 Impact Factor
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ABSTRACT: Tumor suppressor gene (TSG) inactivation by chromosomal deletions and/or mutations is a well-characterized genetic alteration in lymphomas. Array-based technologies have greatly increased the detection and characterization of chromosomal imbalances and regions with loss of heterozygosity (LOH), leading to the identification of a number of novel candidate TSG loci. In addition, microarray platforms for studying DNA methylation and histone modifications enable identifying epigenetic changes affecting gene expression of TSG. Combining these microarray technologies with gene expression profiling is a promising strategy to discover novel TSG in regions targeted by genetic or epigenetic alterations. In this review we present an outline of methodological aspects of the various microarray technologies, and discuss their potentials and restrictions. Furthermore, we survey research findings derived from these high-throughput techniques, which are allowing a deeper insight into the mechanisms of lymphomagenesis.
Apmis 11/2007; 115(10):1107-34. · 1.99 Impact Factor
