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Idoia Martin-Guerrero,
Itziar Salaverria,
Birgit Burkhardt,
Monika Szczepanowski,
Michael Baudis,
Susanne Bens,
Laurence de Leval,
Africa Garcia-Orad,
Heike Horn,
Jasmin Lisfeld,
Shoji Pellissery,
Wolfram Klapper,
Ilske Oschlies,
Reiner Siebert
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ABSTRACT: Pediatric follicular lymphoma is a rare disease that differs genetically and clinically from its adult counterpart. With the exception of pediatric follicular lymphoma with IRF4-translocation, the genetic events associated with these lymphomas have not yet been defined. We applied array-comparative genomic hybridization and molecular inversion probe assay analyses to formalin-fixed paraffin-embedded tissues from 18 patients aged ≤18 years with IRF4 translocation negative follicular lymphoma. All evaluable cases lacked t(14;18). Only six of 16 evaluable cases displayed chromosomal imbalances with gains or amplifications of 6pter-p24.3 (including IRF4) and deletion and copy number neutral-loss of heterozygosity in 1p36 (including TNFRSF14) being most frequent. Sequencing of TNFRSF14 located in the minimal region of loss in 1p36.32 showed nine mutations in seven cases from our series. Two subsets of pediatric follicular lymphoma were delineated according to the presence of molecular alterations, one with genomic aberrations associated with higher grade and/or diffuse-large-B-cell lymphoma component and more widespread disease, and another one lacking genetic alterations associated with more limited disease.
Haematologica 02/2013; · 6.42 Impact Factor
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Itziar Salaverria, Idoia Martin-Guerrero,
Birgit Burkhardt,
Markus Kreuz,
Thorsten Zenz,
Ilske Oschlies,
Norbert Arnold,
Michael Baudis,
Susanne Bens,
Africa García-Orad,
Jasmin Lisfeld,
Carsten Schwaenen,
Monika Szczepanowski,
Swen Wessendorf,
Michael Pfreundschuh,
Lorenz Trümper,
Wolfram Klapper,
Reiner Siebert
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ABSTRACT: Translocations affecting chromosome subband 6p25.3 containing the IRF4 gene have been recently described as characteristic alterations in a molecularly distinct subset of germinal center B-cell-derived lymphomas. Secondary changes have yet only been described in few of these lymphomas. Here, we performed array-comparative genomic hybridization and molecular inversion probe microarray analyses on DNA from 12 formalin-fixed paraffin-embedded and two fresh-frozen IRF4 translocation-positive lymphomas, which together with the previously published data on nine cases allowed the extension of copy number analyses to a total of 23 of these lymphomas. All except one case carried chromosomal imbalances, most frequently gains in Xq28, 11q22.3-qter, and 7q32.1-qter and losses in 6q13-16.1, 15q14-22.31, and 17p. No recurrent copy-neutral losses of heterozygosity were observed. TP53 point mutations were detected in three of six cases with loss of 17p. Overall this study unravels a recurrent pattern of secondary genetic alterations in IRF4 translocation-positive lymphomas. © 2012 Wiley Periodicals, Inc.
Genes Chromosomes and Cancer 10/2012; · 3.31 Impact Factor
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Itziar Salaverria,
Claudia Philipp,
Ilske Oschlies,
Christian W Kohler,
Markus Kreuz,
Monika Szczepanowski,
Birgit Burkhardt,
Heiko Trautmann,
Stefan Gesk,
Miroslaw Andrusiewicz, [......],
Julia Richter,
Maciej Rosolowski,
Carsten Schwaenen,
Harald Stein,
Lorenz Trümper,
Swen Wessendorf,
Rainer Spang,
Ralf Küppers,
Wolfram Klapper,
Reiner Siebert
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ABSTRACT: The prognosis of germinal center-derived B-cell (GCB) lymphomas, including follicular lymphoma and diffuse large-B-cell lymphoma (DLBCL), strongly depends on age. Children have a more favorable outcome than adults. It is not known whether this is because of differences in host characteristics, treatment protocols, or tumor biology, including the presence of chromosomal alterations. By screening for novel IGH translocation partners in pediatric and adult lymphomas, we identified chromosomal translocations juxtaposing the IRF4 oncogene next to one of the immunoglobulin (IG) loci as a novel recurrent aberration in mature B-cell lymphoma. FISH revealed 20 of 427 lymphomas to carry an IG/IRF4-fusion. Those were predominantly GCB-type DLBCL or follicular lymphoma grade 3, shared strong expression of IRF4/MUM1 and BCL6, and lacked PRDM1/BLIMP1 expression and t(14;18)/BCL2 breaks. BCL6 aberrations were common. The gene expression profile of IG/IRF4-positive lymphomas differed from other subtypes of DLBCL. A classifier for IG/IRF4 positivity containing 27 genes allowed accurate prediction. IG/IRF4 positivity was associated with young age and a favorable outcome. Our results suggest IRF4 translocations to be primary alterations in a molecularly defined subset of GCB-derived lymphomas. The probability for this subtype of lymphoma significantly decreases with age, suggesting that diversity in tumor biology might contribute to the age-dependent differences in prognosis of lymphoma.
Blood 04/2011; 118(1):139-47. · 9.90 Impact Factor
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Alexander Herrmann,
Andrea Haake,
Ole Ammerpohl, Idoia Martin-Guerrero,
Karol Szafranski,
Kathryn Stemshorn,
Michael Nothnagel,
Steve K Kotsopoulos,
Julia Richter,
Jason Warner,
Jeff Olson,
Darren R Link,
Stefan Schreiber,
Michael Krawczak,
Matthias Platzer,
Peter Nürnberg,
Reiner Siebert,
Jochen Hampe
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ABSTRACT: Cytosine methylation provides an epigenetic level of cellular plasticity that is important for development, differentiation and cancerogenesis. We adopted microdroplet PCR to bisulfite treated target DNA in combination with second generation sequencing to simultaneously assess DNA sequence and methylation. We show measurement of methylation status in a wide range of target sequences (total 34 kb) with an average coverage of 95% (median 100%) and good correlation to the opposite strand (rho = 0.96) and to pyrosequencing (rho = 0.87). Data from lymphoma and colorectal cancer samples for SNRPN (imprinted gene), FGF6 (demethylated in the cancer samples) and HS3ST2 (methylated in the cancer samples) serve as a proof of principle showing the integration of SNP data and phased DNA-methylation information into "hepitypes" and thus the analysis of DNA methylation phylogeny in the somatic evolution of cancer.
PLoS ONE 01/2011; 6(7):e21332. · 4.09 Impact Factor
