Clinical applicability of targeted next-generation sequencing for precision medicine in diffuse large B-cell lymphoma.

Abstract

e19538 Background: Comprehensive genomic analysis based on next-generation sequencing (NGS) allows a better molecular characterization of diffuse large B-cell lymphoma (DLBCL), offering a roadmap toward precision medicine. Methods: We analyzed somatic alterations of 37 DLBCL tissue or blood samples by a hybridization capture-based NGS panel targeting 188 lymphoma-related genes. Results: Totally, 279 single-nucleotide variants and small insertions or deletions affecting 103 genes were identified, with at least 1 mutation detected in 100% (37/37) of cases. The most frequently mutated genes were those involved in epigenetic modifiers ( DNMT3A, KMT2B and KMT2D), activated signaling ( TYK2, MYD88, NOTCH2 and BCR) and transcription factors/transcriptional regulator ( RUNX1, SPEN, IRF4, KLF2 and ASXL1). Significant co-occurrences were shown between RUNX1 mutations with NOTCH2, IRF4, ARID1A and BCR ( P< 0.05, respectively), BCR and IRF4 ( P< 0.01), etc. Additionally, we analyzed the association of genomic aberrations with clinicopathological features in DLBCL. Patients aged > 60 years harbored less LRP1B mutations than those aged ≤60 years (5.3% vs. 33.3%, P< 0.05). The mutation frequency of TP53 was significantly higher in LDH-high (> 244 U/L) group than that in LDH-low (≤244 U/L) group (40% vs. 6.25%, P< 0.05). Compared with germinal center B-cell (GCB), the mutation frequency of TYK was significantly lower in non-GCB (5% vs. 36.4%, P< 0.05). New potential therapeutic targets ( CREBBP, EP300, EZH2, SMARCB1, CD79A/B, BTK, CARD11, MYD88, THFAIP3, PIK3CA, PTEN and JAK) were identified in 55% (11/20) of newly diagnosed patients and in 41.2% (7/17) of relapsed/refractory patients. Ibrutinib, as a single agent, has demonstrated limited activity in DLBCL with mutant MYD88 and wildtype CD79. In this study, we identified 3 patients with mutant MYD88 and wildtype CD79A/B (8.1%), among whom 2 harbored MYD88 L265P variants and 1 had MYD88 S219C mutation. Conclusions: The utility of mutational profiling may facilitate the identification of potential drug targets, which in turns may represent new therapeutic possibilities.