Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences.
Comprehensive Transcriptome and Mutational Profiling of Endemic Burkitt Lymphoma Reveals EBV Type-Specific Differences.
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DOI：
10.1158/1541-7786.mcr-16-0305
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发表时间：
2017-05
期刊：
影响因子：
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通讯作者：
Bailey JA
中科院分区：
文献类型：
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作者：
Kaymaz Y;Oduor CI;Yu H;Otieno JA;Ong'echa JM;Moormann AM;Bailey JA
地方性Burkitt淋巴瘤(EBL)是赤道非洲疟疾流行地区最常见的儿童癌症，与发达国家发病率较低的散发性Burkitt淋巴瘤(SBL)不同，EBL几乎总是含有Epstein-Barr病毒(EBV)。鉴于这些差异和不同的临床表现和结果，我们试图通过使用RNA测序(RNAseq)研究多原发EBL肿瘤和SBL肿瘤的转录本来进一步了解发病机制。在EBL肿瘤中，根据解剖表现部位、住院存活率和EBV基因组类型，发现最小的表达差异；表明EBL肿瘤是同质性的，没有明显的亚型。应用替代变量分析发现，与1型相比，携带2型EB病毒的EBL肿瘤中免疫蛋白酶体复合体关键基因(PSMB9/β1i、PSMB10/β2i、PSMB8/β5i和PSME2/PA2 8β)的表达显著降低。其次，与以前发表的儿童SBL标本相比，大多数表达和通路差异与PTEN/PI3K/mTOR信号通路有关，并且与EBV状态的相关性最强，而不是地理位置。第三，在携带EBV 1型的EBL肿瘤中观察到的常见突变明显较少，EBV 2型与不携带EBV的肿瘤之间的突变频率相似。除已报道的基因外，还发现了一组新的突变基因，包括TFAP4、MSH6、PRRC2C、BCL7A、FOXO1、PLCG2、PRKDC、Rad50和RPRD2。总体而言，这些数据证实，EBV，特别是EBV 1型，支持BL肿瘤发生，减轻了对人类基因组中某些驱动突变的需求。
Endemic Burkitt lymphoma (eBL) is the most common pediatric cancer in malaria-endemic equatorial Africa and nearly always contains Epstein-Barr virus (EBV), unlike sporadic Burkitt Lymphoma (sBL) that occurs with a lower incidence in developed countries. Given these differences and the variable clinical presentation and outcomes, we sought to further understand pathogenesis by investigating transcriptomes using RNA sequencing (RNAseq) from multiple primary eBL tumors compared to sBL tumors. Within eBL tumors, minimal expression differences were found based on: anatomical presentation site, in-hospital survival rates, and EBV genome type; suggesting that eBL tumors are homogeneous without marked subtypes. The outstanding difference detected using surrogate variable analysis was the significantly decreased expression of key genes in the immunoproteasome complex (PSMB9/β1i, PSMB10/β2i, PSMB8/β5i, and PSME2/PA28β) in eBL tumors carrying type 2 EBV compared to type 1 EBV. Secondly, in comparison to previously published pediatric sBL specimens, the majority of the expression and pathway differences was related to the PTEN/PI3K/mTOR signaling pathway and was correlated most strongly with EBV status rather than geographic designation. Third, common mutations were observed significantly less frequently in eBL tumors harboring EBV type 1, with mutation frequencies similar between tumors with EBV type 2 and without EBV. In addition to the previously reported genes, a set of new genes mutated in BL including TFAP4, MSH6, PRRC2C, BCL7A, FOXO1, PLCG2, PRKDC, RAD50, and RPRD2 were identified. Overall, these data establish that EBV, particularly EBV type 1, supports BL oncogenesis alleviating the need for certain driver mutations in the human genome.