Integrative Genomic Profiling Reveals Conserved Genetic Mechanisms for Tumorigenesis in Common Entities of Non-Hodgkin's Lymphoma
Integrative Genomic Profiling Reveals Conserved Genetic Mechanisms for Tumorigenesis in Common Entities of Non-Hodgkin's Lymphoma
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DOI：
10.1002/gcc.20856
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发表时间：
2011-05-01
影响因子：
3.7
通讯作者：
Griffiths, Lyn R.
中科院分区：
文献类型：
--
作者：
Green, Michael R.;Aya-Bonilla, Carlos;Griffiths, Lyn R.
基因组技术的最新发展使人们对致病机制有了更多的了解，并强调了中心生存途径的重要性。在这里，我们使用一种新的生物信息学为基础的综合基因组分析方法来阐明保守的机制，淋巴瘤发生在三个最常见的非霍奇金淋巴瘤（NHL）的实体：弥漫性大B细胞淋巴瘤，滤泡性淋巴瘤，B细胞慢性淋巴细胞白血病。通过整合全基因组DNA拷贝数分析和肿瘤队列的转录组分析，我们确定了每个实体中存在的遗传病变，并突出了它们可能的靶基因。这揭示了细胞凋亡途径和有丝分裂原活化蛋白激酶途径的组分的显著富集，包括在所有三个实体中的MAP 3 K12位点的扩增，在这些疾病中的遗传改变靶向的基因组内。此外，12p13.33的扩增在所有三个实体中被鉴定，并发现靶向FOXM 1癌基因。随后发现FOXM 1的扩增与增加的MYC致癌信号特征相关，siRNA介导的FOXM 1敲低导致MYC表达减少并诱导G2阻滞。总之，这些发现强调了MAPK和凋亡途径的遗传改变，以及FOXM 1的遗传扩增作为常见NHL实体中淋巴瘤发生的保守机制。综合基因组分析确定了常见的中心生存机制，并强调它们是定向治疗的有吸引力的靶点。(C)2011 Wiley-Liss，Inc.
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 knockdown 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. (C) 2011 Wiley-Liss, Inc.