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  • Original Article
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Lymphoma

Pathway activation patterns in diffuse large B-cell lymphomas

Abstract

Deregulation of cell signaling pathways controlling cell growth and cell survival is a common feature of all cancers. Although a core repertoire of oncogenic mechanisms is widely conserved between various malignancies, the constellation of pathway activities can vary even in patients with the same malignant disease. Modern molecularly targeted cancer drugs intervene in cell signaling compensating for pathway deregulation. Hence characterizing tumors with respect to pathway activation will become crucial for treatment decisions. Here we have used semi-supervised machine learning methodology to generate signatures of eight oncogene-inducible pathways, which are conserved across epithelial and lymphoid tissues. We combined them to patterns of pathway activity called PAPs for pathway activation patterns and searched for them in 220 morphologically, immunohistochemically and genetically well-characterized mature aggressive B-cell lymphomas including 134 cases with clinical data available. Besides Burkitt lymphoma, which was characterized by a unique pattern, the PAPs identified four distinct groups of mature aggressive B-cell lymphomas across independent gene expression studies with distinct biological characteristics, genetic aberrations and prognosis. We confirmed our findings through cross-platform analysis in an independent data set of 303 mature aggressive B-cell lymphomas.

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Gene Expression Omnibus

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Acknowledgements

This work was carried out within the framework of the research network ‘Molecular Mechanisms in Malignant Lymphoma’ (MMML), supported by the Deutsche Krebshilfe (70-3173-Tr3). In addition R Spang announces support by the Bavarian Genome Network BayGene and AHB is supported by the Leukaemia Research Fund.

Members of MMML project are: Pathology group: Wolfram Klapper, Monika Szcepanowski, Thomas Barth, Wolfram Bernd, Alfred Feller, Martin-Leo Hansmann, Peter Möller, German Ott, Hans-Konrad Müller-Hermelink, Andreas Rosenwald, Hans-Heinrich Wacker, Sergio Cogliatti, Michael Hummel, Harald Stein. Genetics group: Carsten Schwaenen, Swen Wessendorf, Heiko Trautmann, Jose-Ignacio Martin-Subero, Eugenia Haralambieva, Judith Dierlamm, German Ott, Andreas Rosenwald, Thomas Barth, Christiane Pott, Ralf Küppers, Reiner Siebert. Bioinformatics group: Maciej Rosolowski, Rainer Spang, Hilmar Berger, Stefan Bentink, Dirk Hasenclever, Markus Loeffler. Project coordination: Benjamin Stürzenhofecker, Hilmar Berger, Michael Hummel, Lorenz Trümper. Steering Committee: Reiner Siebert, Harald Stein, Markus Loeffler, Lorenz Trümper.

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Correspondence to R Siebert or R Spang.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Bentink, S., Wessendorf, S., Schwaenen, C. et al. Pathway activation patterns in diffuse large B-cell lymphomas. Leukemia 22, 1746–1754 (2008). https://doi.org/10.1038/leu.2008.166

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