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Gain of chromosome region 18q21 including the MALT1 gene is associated with the activated B-cell-like gene expression subtype and increased BCL2 gene dosage and protein expression in diffuse large B-cell lymphoma

¹ Dept. of Oncology and Hematology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
² Max Planck Institute for Molecular Genetics, Computational Diagnostics Group, Berlin, Germany
³ Dept. of Internal Medicine III, Hematology and Oncology, University Hospital Ulm, Ulm, Germany
⁴ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
⁵ Institute of Pathology, Campus Benjamin Franklin, Charité-University Medicine Berlin, Berlin, Germany
⁶ Dept. of Pathology, Hematology Section and Lymph Node Registry, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
⁷ Institute of Pathology, University of Würzburg, Würzburg, Germany
⁸ Institute of Pathology, Kantonsspital St. Gallen, St. Gallen, Switzerland
⁹ Institute of Pathology, University of Ulm, Ulm, Germany
¹⁰ Department of Hematology, University Hospital Göttingen, Göttingen, Germany and
¹¹ Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany

Correspondence: Judith Dierlamm, M.D., Ph.D., Department of Oncology and Hematology with the sections of Bone Marrow Transplantation and Pneumology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany. E-mail: judith_dierlamm{at}yahoo.de

Background: The aim of this study was to determine the impact of a gain of the MALT1 gene on gene expression and clinical parameters in diffuse large B-cell lymphoma.

Design and Methods: We analyzed 116 cases of diffuse large B-cell lymphoma by fluorescence in situ hybridization, array-based comparative genomic hybridization, and transcriptional profiling.

Results: A gain of 18q21 including MALT1 was detected in 44 cases (38%) and was accompanied by a gain of BCL2 in 43 cases. All cases with a 18q21/MALT1 gain showed BCL2 protein whereas 79% in the group without a 18q21/MALT1 gain did so (p<0.001). Cases with 18q21/MALT1 gain more frequently showed an activated B-cell-like (ABC) gene expression signature (65%) than a germinal center B-cell-like (GCB) one (23%) (p<0.001). Ninety-eight genes including MALT1, BCL2, and some selected nuclear factor-B target genes were differentially expressed between the two genetic groups of diffuse large B-cell lymphoma. By global testing of each chromosome, we identified 33 genes, all located on chromosome 18q, which were differentially expressed between the two genetic groups independently of the ABC/GCB status. In multivariate analysis, the 18q21/MALT1 status represented an independent negative prognostic factor for overall survival (p=0.03).

Conclusions: In diffuse large B-cell lymphoma, gain of 18q21 including MALT1 is significantly associated with differential expression of genes located on 18q, the ABC gene expression subtype, increased BCL2 gene and protein expression and might indicate an unfavorable prognosis.

Key words: MALT1, BCL2, gene expression, prognosis, diffuse large B-cell lymphoma.

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