Massive Transcriptional Perturbation in Subgroups of Diffuse Large B-cell Lymphomas

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.

基于癌症发生过程中涉及的分子机制以协调表达基因群为特征之假设，本研究团队开发并验证了一种新型转录数据分析方法，称之为关联基因集分析（Correlated Gene Set Analysis，简称CGSA）。通过从50个提取的基因集中进行分析，我们在包含364例弥漫性大B细胞淋巴瘤（Diffuse large B-cell lymphoma，简称DLBCL）及其相关成熟侵袭性B细胞淋巴瘤（除Burkitt淋巴瘤外）的队列中，鉴定出三种不同的肿瘤表型。第一种表型表现为与增殖相关的基因高表达；第二种表型则展现出基质和免疫反应表型。这两种表型均以大规模基因激活为特征，影响了近期研究发现受表观遗传调控的基因，这些基因富集于氧化磷酸化、能量代谢和核苷酸生物合成途径。第三种新颖的表型仅表现出与正常B细胞相似的轻度全局基因激活，而在细胞系中则未发现。本研究揭示了DLBCL在低或高大规模基因激活方面的新颖复杂性，这些激活与代谢和生物合成相关，并且在高度激活的DLBCL群体中，表现出导致增殖或基质和免疫反应表型的差异行为。