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

Aurelia Ada Guarini, Claudio Tripodo, Fabbri, Derenzini, Chiappella, Ciavarella, Alessandro M. Gianni, Loseto, De Summa, Tabanelli, Casadei, Vegliante, Stefano Aldo Pileri, Zito, Opinto, Melle, Corrado Tarella, Rivas-Delgado, Campo, VenesioDe Iuliis, Ingravallo, Rega, Fiori, Mele, Tarella, Tripodo, Scattone, Claudio Agostinelli, Umberto Vitolo, Stefania Tommasi, Attilio Guarini, López-Guillermo, Rambaldi, Sapino, Anita Mangia, Zito, Giovanni Simone, Pileri, Zinzani, Motta, Enjuanes

Risultato della ricerca: Articlepeer review

19 Citazioni (Scopus)


Background: 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. Patients and methods: 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. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4þ 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 þ 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. Conclusions: 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.
Lingua originaleEnglish
pagine (da-a)2363-2370
Numero di pagine8
RivistaAnnals of Oncology
Stato di pubblicazionePublished - 2018

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology

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