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

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BlankIntegrative genomic profiling reveals conserved genetic mechanisms for

tumorigenesis in common entities of non-Hodgkin's lymphoma.

MR Green, C Aya-Bonilla, MK Gandhi, RA Lea, J Wellwood, P Wood, P Marlton, and

LR Griffiths

Genes Chromosomes Cancer, February 8, 2011;

Genomics Research Centre, Griffith Health Institute, Griffith University, QLD,

Australia; Griffith Medical Research College, A joint initiative of the Griffith

Institute of Health & Medical Research and the Queensland Institute of Medical

Research, 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 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.

PMID: 21305641