Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets.
Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets.
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DOI：
10.1038/leu.2017.251
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Campo E
中科院分区：
文献类型：
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作者：
Karube K;Enjuanes A;Dlouhy I;Jares P;Martin-Garcia D;Nadeu F;Ordóñez GR;Rovira J;Clot G;Royo C;Navarro A;Gonzalez-Farre B;Vaghefi A;Castellano G;Rubio-Perez C;Tamborero D;Briones J;Salar A;Sancho JM;Mercadal S;Gonzalez-Barca E;Escoda L;Miyoshi H;Ohshima K;Miyawaki K;Kato K;Akashi K;Mozos A;Colomo L;Alcoceba M;Valera A;Carrió A;Costa D;Lopez-Bigas N;Schmitz R;Staudt LM;Salaverria I;López-Guillermo A;Campo E
弥漫性大b细胞淋巴瘤（DLBCL）的基因组研究揭示了大量的体细胞突变和结构改变。然而，这些改变的临床意义仍然没有很好的定义。在这项研究中，我们整合了150例DLBCL的106个基因的靶向下一代测序和基因组拷贝数改变（CNA）分析。具有临床意义的发现在111例患者的独立队列中得到了验证。生发中心b细胞和活化b细胞DLBCL在突变、致病途径和CNA方面存在差异。在独立验证队列中证实，NOTCH通路和肿瘤抑制基因（TP53/CDKN2A）的基因突变（而非单个基因）会导致不良预后。基因表达谱分析显示，NOTCH通路突变的肿瘤具有显著的下游靶基因调控，强调了该通路在DLBCL中的相关性。一项计算机药物发现分析确认了69例（46%）携带至少一种基因组改变的病例，根据早期临床试验或临床前分析，DLBCL或其他淋巴瘤被认为是药物反应的潜在靶点。总之，本研究确定了DLBCL的相关通路和突变基因，并确定了新的干预策略的潜在靶点。
Genome studies of diffuse large B-cell lymphoma (DLBCL) have revealed a large number of somatic mutations and structural alterations. However, the clinical significance of these alterations is still not well defined. In this study, we have integrated the analysis of targeted next-generation sequencing of 106 genes and genomic copy number alterations (CNA) in 150 DLBCL. The clinically significant findings were validated in an independent cohort of 111 patients. Germinal center B-cell and activated B-cell DLBCL had a differential profile of mutations, altered pathogenic pathways and CNA. Mutations in genes of the NOTCH pathway and tumor suppressor genes (TP53/CDKN2A), but not individual genes, conferred an unfavorable prognosis, confirmed in the independent validation cohort. A gene expression profiling analysis showed that tumors with NOTCH pathway mutations had a significant modulation of downstream target genes, emphasizing the relevance of this pathway in DLBCL. An in silico drug discovery analysis recognized 69 (46%) cases carrying at least one genomic alteration considered a potential target of drug response according to early clinical trials or preclinical assays in DLBCL or other lymphomas. In conclusion, this study identifies relevant pathways and mutated genes in DLBCL and recognizes potential targets for new intervention strategies.
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影响因子：
50.3
作者：
Monti S;Chapuy B;Takeyama K;Rodig SJ;Hao Y;Yeda KT;Inguilizian H;Mermel C;Currie T;Dogan A;Kutok JL;Beroukhim R;Neuberg D;Habermann TM;Getz G;Kung AL;Golub TR;Shipp MA
通讯作者：
Shipp MA
弥漫性大B细胞淋巴瘤中CD58和TP53基因的突变或拷贝数丢失是独立的不利预后因素
影响因子：
--
作者：
Cao Y;Zhu T;Zhang P;Xiao M;Yi S;Yang Y;Li Q;Ling S;Wang Y;Gao L;Zhu L;Wang J;Wang N;Huang L;Zhang P;Zhai Q;Qiu L;Zhou J
通讯作者：
Zhou J
影响因子：
20.3
作者：
Chan, Fong Chun;Telenius, Adele;Steidl, Christian
通讯作者：
Steidl, Christian
影响因子：
3.7
作者：
Mo JS;Yoon JH;Hong JA;Kim MY;Ann EJ;Ahn JS;Kim SM;Baek HJ;Lang F;Choi EJ;Park HS
通讯作者：
Park HS
影响因子：
28.2
作者：
Dienstmann R;Jang IS;Bot B;Friend S;Guinney J
通讯作者：
Guinney J