Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue

被引：93

作者：

Ciavarella, S. ^{[1
]}

Vegliante, M. C. ^{[1
]}

Fabbri, M. ^{[2
]}

De Summa, S. ^{[3
]}

Melle, F. ^{[2
]}

Motta, G. ^{[2
]}

De Iuliis, V. ^{[4
]}

Opinto, G. ^{[5
]}

Enjuanes, A. ^{[6
,7
]}

Rega, S. ^{[8
]}

Gulino, A. ^{[9
]}

Agostinelli, C. ^{[10
]}

Scattone, A. ^{[8
]}

Tommasi, S. ^{[3
]}

Mangia, A. ^{[5
]}

Mele, F. ^{[8
]}

Simone, G. ^{[8
]}

Zito, A. F. ^{[8
]}

Ingravallo, G. ^{[11
]}

Vitolo, U. ^{[12
]}

Chiappella, A. ^{[12
]}

Tarella, C. ^{[13
]}

Gianni, A. M. ^{[13
]}

Rambaldi, A. ^{[14
,15
]}

Zinzani, P. L. ^{[10
]}

Casadei, B. ^{[10
]}

Derenzini, E. ^{[13
]}

Loseto, G. ^{[1
]}

Pileri, A. ^{[10
]}

Tabanelli, V. ^{[2
]}

Fiori, S. ^{[2
]}

Rivas-Delgado, A. ^{[7
,16
,17
]}

Lopez-Guillermo, A. ^{[7
,16
,17
]}

Venesio, T. ^{[18
]}

Sapino, A. ^{[18
]}

Campo, E. ^{[7
,19
,20
]}

Tripodo, C. ^{[8
]}

Guarini, A. ^{[1
]}

Pileri, S. A. ^{[2
]}

机构：

[1] IRCCS Ist Tumori Giovanni Paolo II, Hematol & Cell Therapy Unit, Bari, Italy

[2] European Inst Oncol, IRCCS, Div Diagnost Haematopathol, Via Giuseppe Ripamonti 435, I-20141 Milan, Italy

[3] IRCCS Ist Tumori Giovanni Paolo II, Mol Diagnost & Pharmacogenet Unit, Bari, Italy

[4] Univ G dAnnunzio, Postgrad Med Sch Clin Pathol, Chieti, Italy

[5] IRCCS Ist Tumori Giovanni Paolo II, Funct Biomorphol Lab, Bari, Italy

[6] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Unitat Genom, Barcelona, Spain

[7] CIBERONC, Barcelona, Spain

[8] IRCCS Ist Tumori Giovanni Paolo II, Pathol Dept, Bari, Italy

[9] Univ Palermo, Dipartimento Promoz Salute & Materno Infantile G, Tumor Immunol Unit, Palermo, Italy

[10] Bologna Univ, Sch Med, Dept Expt Diagnost & Specialty Med DIMES, Bologna, Italy

[11] Univ Bari Aldo Moro, Dept Emergency & Organ Transplantat DETO, Pathol Sect, Bari, Italy

[12] Azienda Osped Univ Citta Salute & Sci Torino, Dept Hematol, Turin, Italy

[13] European Inst Oncol, IRCCS, Oncohematol Unit, Milan, Italy

[14] Azienda Socio Sanit Terr Papa Giovanni XXIII, Dept Hematol & Oncol, Bergamo, Italy

[15] Univ Milan, Sch Med, Milan, Italy

[16] Hosp Clin Barcelona, Hematol Dept, Barcelona, Spain

[17] IDIBAPS, Barcelona, Spain

[18] Candiolo Canc Inst, Pathol Dept, Turin, Italy

[19] Hosp Clin Barcelona, Dept Pathol, Haematopathol Unit, Barcelona, Spain

[20] Univ Barcelona, Barcelona, Spain

来源：

ANNALS OF ONCOLOGY | 2018年 / 29卷 / 12期

关键词：

DLBCL; microenvironment; deconvolution; cell-of-origin; digital expression analysis; prognosticators; B-CELL LYMPHOMA; R-CHOP; CHEMOTHERAPY; DEREGULATION; SIGNATURES; STROMA; TUMOR;

D O I：

10.1093/annonc/mdy450

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：2363 / 2370

页数：8

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