Abstract
Based on the assumption that molecular mechanisms involved in cancerogenesis are characterized by groups of coordinately expressed genes, we developed and validated a novel method for analyzing transcriptional data called Correlated Gene Set Analysis (CGSA). Using 50 extracted gene sets we identified three different profiles of tumors in a cohort of 364 Diffuse large B-cell (DLBCL) and related mature aggressive B-cell lymphomas other than Burkitt lymphoma. The first profile had high level of expression of genes related to proliferation whereas the second profile exhibited a stromal and immune response phenotype. These two profiles were characterized by a large scale gene activation affecting genes which were recently shown to be epigenetically regulated, and which were enriched in oxidative phosphorylation, energy metabolism and nucleoside biosynthesis. The third and novel profile showed only low global gene activation similar to that found in normal B cells but not cell lines. Our study indicates novel levels of complexity of DLBCL with low or high large scale gene activation related to metabolism and biosynthesis and, within the group of highly activated DLBCLs, differential behavior leading to either a proliferative or a stromal and immune response phenotype.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease [1,2,3,4,5,6]
These include the cell of origin signatures for activated B-cell-like diffuse large B-cell lymphomas (ABC) and the germinal center B-cell-like diffuse large B-cell lymphomas (GCB) [1,2], the ‘‘consensus clusters’’ [3] referred to as ‘‘oxidative phosphorylation’’ (OxPhos), ‘‘B-cell receptor/proliferation’’ (BCR) and ‘‘host response’’ (HR), and the ‘‘pathway activation patterns’’ [6] (PAPs) denoted by PAP-1 to PAP-4, BL-PAP and ‘‘molecularly individual lymphomas’’
We developed a novel method called Correlated Gene Set Analysis (CGSA) for unbiased and hypothesis-free analysis of large gene expression data sets
Summary
Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous disease [1,2,3,4,5,6]. The heterogeneity of DLBCL as that of several other types of cancer is believed to arise as a consequence of a number of aberrations causing different patterns of deregulation of cell signaling pathways [11,14]. This view suggests that groups of coexpressed genes which are expected to be observed as a result of deregulation of signaling pathways, may carry most of the information about the heterogeneity of tumors. These gene sets can be used in subsequent analyses, e.g., tests for association with other phenotypes and in unsupervised analysis of the samples
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