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Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study

Sydney Dubois 1 Pierre-Julien Viailly 1, 2 Sylvain Mareschal 1 Elodie Bohers 1 Philippe Bertrand 1 Philippe Ruminy 1 Catherine Maingonnat 1 Jean-Philippe Jais 3, 4 Pauline Peyrouze 5 Martin Figeac 6, 5 Thierry J. Molina 7 Fabienne Desmots 8, 9 Thierry Fest 8, 9 Corinne Haioun 10 Thierry Lamy 9, 8 Christiane Copie-Bergman 11 Josette Brière 12, 13 Tony Petrella 14 Danielle Canioni 7, 15 Bettina Fabiani 16 Bertrand Coiffier 17, 18 Richard Delarue 19 Frederic Peyrade 20 André Bosly 21 Marc André 21 Nicolas Ketterer 22 Gilles Salles 23, 18 Hervé Tilly 1 Karen Leroy 24, 25 Fabrice Jardin 1, *
Abstract : Purpose: Next-generation sequencing (NGS) has detailed the genomic characterization of diffuse large B-cell lymphoma (DLBCL) by identifying recurrent somatic mutations. We set out to design a clinically feasible NGS panel focusing on genes whose mutations hold potential therapeutic impact. Furthermore, for the first time, we evaluated the prognostic value of these mutations in prospective clinical trials. Experimental Design: A Lymphopanel was designed to identify mutations in 34 genes, selected according to literature and a whole exome sequencing study of relapsed/refractory DLBCL patients. The tumor DNA of 215 patients with CD20(+)de novo DLBCL in the prospective, multicenter, and randomized LNH-03B LYSA clinical trials was sequenced to deep, uniform coverage with the Lymphopanel. Cell-of-origin molecular classification was obtained through gene expression profiling with HGU133+2.0 Affymetrix GeneChip arrays. Results: The Lymphopanel was informative for 96% of patients. A clear depiction of DLBCL subtype molecular heterogeneity was uncovered with the Lymphopanel, confirming that activated B-cell-like (ABC), germinal center B-cell like (GCB), and primary mediastinal B-cell lymphoma (PMBL) are frequently affected by mutations in NF-kappa B, epigenetic, and JAK-STAT pathways, respectively. Novel truncating immunity pathway, ITPKB, MFHAS1, and XPO1 mutations were identified as highly enriched in PMBL. Notably, TNFAIP3 and GNA13 mutations in ABC patients treated with RCHOP were associated with significantly less favorable prognoses. Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting the molecular heterogeneity of subtypes and identifying somatic mutations with therapeutic and prognostic impact. (C) 2016 AACR.
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Submitted on : Thursday, December 15, 2016 - 2:57:35 PM
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Sydney Dubois, Pierre-Julien Viailly, Sylvain Mareschal, Elodie Bohers, Philippe Bertrand, et al.. Next-Generation Sequencing in Diffuse Large B-Cell Lymphoma Highlights Molecular Divergence and Therapeutic Opportunities: a LYSA Study. Clinical Cancer Research, American Association for Cancer Research, 2016, 22 (12), pp.2919--2928. ⟨10.1158/1078-0432.CCR-15-2305⟩. ⟨hal-01343064⟩

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