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

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 data 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 NFkB, 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. Conclusions: This study demonstrates the contribution of NGS with a consensus gene panel to personalized therapy in DLBCL, highlighting subtypes' molecular heterogeneity and identifying somatic mutations with therapeutic and prognostic impact.

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