• Sydney Dubois, Pierre-Julien Viailly, Sylvain Mareschal, Elodie Bohers, Philippe Bertrand, Philippe Ruminy, Catherine Maingonnat, Jean-Philippe Jais, Pauline Peyrouze, Martin Figeac, Thierry J Molina, Fabienne Desmots, Thierry Fest, Corinne Haioun, Thierry Lamy, Christiane Copie-Bergman, Josette Brière, Tony Petrella, Danielle Canioni, Bettina Fabiani, Bertrand Coiffier, Richard Delarue, Frédéric Peyrade, André Bosly, Marc André, Nicolas Ketterer, Gilles Salles, Hervé Tilly, Karen Leroy, and Fabrice Jardin.
• Inserm U918, Centre Henri Becquerel, Université de Rouen, IRIB, Rouen, France.
• Clin Cancer Res. 2016 Jun 15; 22 (12): 2919-28.

PurposeNext-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 DesignA 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.ResultsThe 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-κB, 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 R-CHOP were associated with significantly less favorable prognoses.ConclusionsThis 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. Clin Cancer Res; 22(12); 2919-28. ©2016 AACRSee related commentary by Lim and Elenitoba-Johnson, p. 2829.©2016 American Association for Cancer Research.

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