title: Integrative genomic profiling reveals conserved genetic mechanisms for tumorigenesis in common entities of non-Hodgkin's lymphoma.
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.
authors.affiliation: Genomics Research Centre, Griffith Health Institute, Griffith University, QLD, Australia.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Green
authors.forename: Carlos
authors.initials: C
authors.lastname: Aya-Bonilla
authors.forename: Maher K
authors.initials: MK
authors.lastname: Gandhi
authors.forename: Rod A
authors.initials: RA
authors.lastname: Lea
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wellwood
authors.forename: Peter
authors.initials: P
authors.lastname: Wood
authors.forename: Paula
authors.initials: P
authors.lastname: Marlton
authors.forename: Lyn R
authors.initials: LR
authors.lastname: Griffiths
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015331:Cohort Studies; D019295:Computational Biology / Q000379:methods; D056915:DNA Copy Number Variations; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D016195:G2 Phase / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D016259:Genes, myc; D016678:Genome; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016196:S Phase / Q000235:genetics
chemical_list: C107585:FOXM1 protein, human; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C090757:mitogen-activated protein kinase kinase kinase 12