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Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin's lymphoma

Authors

  • Michael R. Green,

    1. Genomics Research Centre, Griffith Health Institute, Griffith University, QLD, Australia
    2. Griffith Medical Research College, A joint initiative of the Griffith Institute of Health & Medical Research and the Queensland Institute of Medical Research, QLD, Australia
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  • Carlos Aya-Bonilla,

    1. Genomics Research Centre, Griffith Health Institute, Griffith University, QLD, Australia
    2. Griffith Medical Research College, A joint initiative of the Griffith Institute of Health & Medical Research and the Queensland Institute of Medical Research, QLD, Australia
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  • Maher K. Gandhi,

    1. Griffith Medical Research College, A joint initiative of the Griffith Institute of Health & Medical Research and the Queensland Institute of Medical Research, QLD, Australia
    2. Clinical Immunohaematology Laboratory, Queensland Institute of Medical Research, QLD, Australia
    3. Princess Alexandra, Queensland Health, QLD, Australia
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  • Rod A. Lea,

    1. Genomics Research Centre, Griffith Health Institute, Griffith University, QLD, Australia
    2. Griffith Medical Research College, A joint initiative of the Griffith Institute of Health & Medical Research and the Queensland Institute of Medical Research, QLD, Australia
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  • Jeremy Wellwood,

    1. Gold Coast Hospitals, Queensland Health, QLD, Australia
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  • Peter Wood,

    1. Princess Alexandra, Queensland Health, QLD, Australia
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  • Paula Marlton,

    1. Princess Alexandra, Queensland Health, QLD, Australia
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  • Lyn R. Griffiths

    Corresponding author
    1. Genomics Research Centre, Griffith Health Institute, Griffith University, QLD, Australia
    2. Griffith Medical Research College, A joint initiative of the Griffith Institute of Health & Medical Research and the Queensland Institute of Medical Research, QLD, Australia
    • Genomics Research Centre, Griffith Institute of Health & Medical Research, Griffith University, Parklands Drive, Southport, QLD 4215, Australia
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Abstract

Recent developments in genomic technologies have resulted in increased understanding of pathogenic mechanisms and emphasized the importance of central survival pathways. Here, we use a novel bioinformatic based integrative genomic profiling approach to elucidate conserved mechanisms of lymphomagenesis in the three commonest non-Hodgkin's lymphoma (NHL) entities: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. By integrating genome-wide DNA copy number analysis and transcriptome profiling of tumor cohorts, we identified genetic lesions present in each entity and highlighted their likely target genes. This revealed a significant enrichment of components of both the apoptosis pathway and the mitogen activated protein kinase pathway, including amplification of the MAP3K12 locus in all three entities, within the set of genes targeted by genetic alterations in these diseases. Furthermore, amplification of 12p13.33 was identified in all three entities and found to target the FOXM1 oncogene. Amplification of FOXM1 was subsequently found to be associated with an increased MYC oncogenic signaling signature, and siRNA-mediated knock-down of FOXM1 resulted in decreased MYC expression and induced G2 arrest. Together, these findings underscore genetic alteration of the MAPK and apoptosis pathways, and genetic amplification of FOXM1 as conserved mechanisms of lymphomagenesis in common NHL entities. Integrative genomic profiling identifies common central survival mechanisms and highlights them as attractive targets for directed therapy. © 2011 Wiley-Liss, Inc.

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