Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.
Genetics and Pathogenesis of Diffuse Large B-Cell Lymphoma.
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DOI：
10.1056/nejmoa1801445
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发表时间：
2018-04-12
期刊：
影响因子：
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通讯作者：
Staudt LM
中科院分区：
文献类型：
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作者：
Schmitz R;Wright GW;Huang DW;Johnson CA;Phelan JD;Wang JQ;Roulland S;Kasbekar M;Young RM;Shaffer AL;Hodson DJ;Xiao W;Yu X;Yang Y;Zhao H;Xu W;Liu X;Zhou B;Du W;Chan WC;Jaffe ES;Gascoyne RD;Connors JM;Campo E;Lopez-Guillermo A;Rosenwald A;Ott G;Delabie J;Rimsza LM;Tay Kuang Wei K;Zelenetz AD;Leonard JP;Bartlett NL;Tran B;Shetty J;Zhao Y;Soppet DR;Pittaluga S;Wilson WH;Staudt LM
弥漫性大B细胞淋巴瘤(DLBCL)具有表型和遗传异质性。基因表达谱已根据细胞来源确定了DLBCL的亚群(激活的B细胞样[ABC]、生发中心B细胞样[GCB]和未分类)，这些亚群与化疗和靶向药物的不同反应有关。我们试图通过根据共同的基因组异常识别DLBCL的遗传亚型来扩展这些发现，并揭示基于肿瘤遗传学的治疗脆弱性。我们研究了574个DLBCL活检样本，使用外显子和转录组测序，基于阵列的DNA拷贝数分析，以及372个基因的定向扩增子重测序，以识别有反复异常的基因。我们开发并实现了一种基于基因改变共生的遗传亚型发现算法。我们在DLBCL中发现了四种显著的遗传亚型，分别是MCD(基于MYD88L265P和CD79B突变的共存)、BN2(基于BCL6融合和NOTCH2突变)、N1(基于NOTCH1突变)和EZB(基于EZH2突变和BCL2易位)。多个基因的遗传异常将每个遗传亚型与其他DLBCL区分开来。根据基因表达特征和对免疫化疗反应的不同判断，这些亚型的表型不同，在BN2和EZB亚型中生存良好，在MCD和N1亚型中预后较差。对遗传途径的分析表明，MCD和BN2DLBCL依赖于“慢性激活的”B细胞受体信号，而B细胞受体信号适合于治疗抑制。我们发现DLBCL的遗传亚型具有不同的基因型、表观遗传学和临床特征，为DLBCL的精确医学策略提供了潜在的病因学。(由国立卫生研究院和其他机构的校内研究计划资助。)
Diffuse large B-cell lymphomas (DLBCLs) are phenotypically and genetically heterogeneous. Gene-expression profiling has identified subgroups of DLBCL (activated B-cell–like [ABC], germinal-center B-cell–like [GCB], and unclassified) according to cell of origin that are associated with a differential response to chemotherapy and targeted agents. We sought to extend these findings by identifying genetic subtypes of DLBCL based on shared genomic abnormalities and to uncover therapeutic vulnerabilities based on tumor genetics. We studied 574 DLBCL biopsy samples using exome and transcriptome sequencing, array-based DNA copy-number analysis, and targeted amplicon resequencing of 372 genes to identify genes with recurrent aberrations. We developed and implemented an algorithm to discover genetic subtypes based on the co-occurrence of genetic alterations. We identified four prominent genetic subtypes in DLBCL, termed MCD (based on the co-occurrence of MYD88L265P and CD79B mutations), BN2 (based on BCL6 fusions and NOTCH2 mutations), N1 (based on NOTCH1 mutations), and EZB (based on EZH2 mutations and BCL2 translocations). Genetic aberrations in multiple genes distinguished each genetic subtype from other DLBCLs. These subtypes differed phenotypically, as judged by differences in gene-expression signatures and responses to immunochemotherapy, with favorable survival in the BN2 and EZB subtypes and inferior outcomes in the MCD and N1 subtypes. Analysis of genetic pathways suggested that MCD and BN2 DLBCLs rely on “chronic active” B-cell receptor signaling that is amenable to therapeutic inhibition. We uncovered genetic subtypes of DLBCL with distinct genotypic, epigenetic, and clinical characteristics, providing a potential nosology for precision-medicine strategies in DLBCL. (Funded by the Intramural Research Program of the National Institutes of Health and others.)