GENES, CHROMOSOMES & CANCER 50:313–326 (2011) Integrative Genomic Profiling Reveals Conserved Genetic Mechanisms for Tumorigenesis in Common Entities of Non-Hodgkin’s Lymphoma Michael R. Green, 1,2 Carlos Aya-Bonilla, 1,2 Maher K. Gandhi, 2,3,4 Rod A. Lea, 1,2 Jeremy Wellwood, 5 Peter Wood, 4 Paula Marlton, 4 and Lyn R. Griffiths 1,2 * 1 Genomics Research Centre,Griff|th Health Institute,Griff|th University,QLD, Australia 2 Griff|th Medical Research College, A joint initiative of the Griff|th Institute of Health & Medical Research and the Queensland Institute of Medical Research,QLD, Australia 3 Clinical Immunohaematology Laboratory,Queensland Institute of Medical Research,QLD, Australia 4 Princess Alexandra,Queensland Health,QLD, Australia 5 Gold Coast Hospitals,Queensland Health,QLD, Australia 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 lym- phoma (NHL) entities: diffuse large B-cell lymphoma, follicular lymphoma, and B-cell chronic lymphocytic leukemia. By inte- grating 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, amplifica- tion 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. V V C 2011 Wiley-Liss, Inc. INTRODUCTION Non-Hodgkin’s lymphomas (NHL) are a class of mature B-cell neoplasias that encompass numerous unique diagnostic entities (Harris et al., 1999) with an incidence of 19 new cases per year for every 100,000 people (Fisher and Fisher, 2004). The most common NHL entities are diffuse large B-cell lymphoma (DLBCL), fol- licular lymphoma (FL), and B-cell chronic lym- phocytic leukemia (B-CLL), which account for over 65% of all cases (Jayasekara et al., 2010). DLBCL is an aggressive disease, whereas FL and B-CLL are indolent diseases. However, the linked etiology of these malignancies is high- lighted by the capacity of FL and B-CLL to undergo transformation to an aggressive DLBCL- like disease (O’Brien et al., 1995; Martinez-Cli- ment et al., 2003). Furthermore, FL and B-CLL also share a relationship to DLBCL in terms of differentiation state; FL and 50% of DLBCLs are related to a normal germinal centre B-cells, whereas B-CLL and 30% of DLBCLs are related to antigen-experienced (activated) or memory B-cells (Shaffer et al., 2002; Kuppers, 2005). In comparison to solid tumors, B-cell lympho- mas do not acquire a large frequency of somatic DNA sequence alterations such as TP53 mutation (Kuppers, 2005; Greenman et al., 2007). Instead, much of the molecular pathogenesis of these malignancies is driven by chromosomal aberra- tions such as translocations and DNA copy Additional Supporting Information may be found in the online version of this article. Supported by: The Griffith Medical Research College, The Herbert Family, and The Queensland Cancer Council. *Correspondence to: Lyn R. Griffiths, Genomics Research Centre, Griffith Institute of Health & Medical Research, Griffith University, Parklands Drive, Southport, QLD 4215, Australia. E-mail: l.griffiths@griffith.edu.au Received 4 November 2010; Accepted 7 January 2011 DOI 10.1002/gcc.20856 Published online 8 February 2011 in Wiley Online Library (wileyonlinelibrary.com). V V C 2011 Wiley-Liss, Inc.