Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue.
Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue.
复制标题
DOI：
10.1093/annonc/mdy450
复制
发表时间：
2018-12-01
期刊：
影响因子：
--
通讯作者：
Pileri SA
中科院分区：
文献类型：
--
作者：
Ciavarella S;Vegliante MC;Fabbri M;De Summa S;Melle F;Motta G;De Iuliis V;Opinto G;Enjuanes A;Rega S;Gulino A;Agostinelli C;Scattone A;Tommasi S;Mangia A;Mele F;Simone G;Zito AF;Ingravallo G;Vitolo U;Chiappella A;Tarella C;Gianni AM;Rambaldi A;Zinzani PL;Casadei B;Derenzini E;Loseto G;Pileri A;Tabanelli V;Fiori S;Rivas-Delgado A;López-Guillermo A;Venesio T;Sapino A;Campo E;Tripodo C;Guarini A;Pileri SA
基因表达谱（GEP）研究认识到肿瘤微环境（TME）在弥漫性大B细胞淋巴瘤（DLBCL）中的预后作用，但常规采用预后间质特征仍然有限。在这里，我们应用计算方法CIBERSORT生成了包含17种免疫和基质细胞型特征的1028个基因矩阵。然后，我们对482例未经治疗的DLBCL的公开GEP数据进行了去卷积，以揭示临床结果与假定肿瘤浸润细胞类型比例之间的相关性。选择了45个与特异性预后细胞型相关的基因，并通过NanoString技术对来自两项随机试验的175个福尔马林固定、石蜡包埋DLBCL的验证集进行数字量化。从一个无监督的聚类分析的数据被用来建立一个模型的聚类分配，其预后价值也评估了一个独立的队列的40例。所有组织样本均由通过可比的R-CHOP/R-CHOP样方案治疗的晚期DLBCL的预处理活检组成。 计算机模拟分析表明，较高比例的肌成纤维细胞（MF）、树突状细胞和CD 4 + T细胞与更好的结局相关，并且我们的小组中的基因表达与总体和无进展生存期的风险相关。在多变量考克斯模型中，微环境基因独立于细胞来源（COO）保持了高预后性能，并且两个预测因子（COO + TME）的整合改善了验证集和独立队列中的生存预测。此外，MF相关基因对面板和基因集富集分析的主要贡献表明DLBCL生物学中细胞外基质决定簇的强烈影响。我们的研究确定了DLBCL的新预后类别，提供了一个易于应用的基因面板，有力地预测患者的生存。此外，由于其与特定基质和免疫组分的关系，该小组可能在探索对TME具有已知影响的新药的临床试验中获得预测相关性。
Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients’ survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.
登录
查看更多内容
影响因子：
5.5
作者：
Abdou AG;Asaad N;Kandil M;Shabaan M;Shams A
通讯作者：
Shams A
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
影响因子：
20.3
作者：
Alizadeh, Ash A.;Gentles, Andrew J.;Levy, Ronald
通讯作者：
Levy, Ronald
DOI：
10.3324/haematol.2010.037408
发表时间：
2011-07-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Cardesa-Salzmann, Teresa M.;Colomo, Luis;Campo, Elias
通讯作者：
Campo, Elias
影响因子：
3.5
作者：
Meyer, Paul N.;Fu, Kai;Weisenburger, Dennis D.
通讯作者：
Weisenburger, Dennis D.