Biological and Clinical Relevance of Associated Genomic Alterations in MYD88 L265P and non-L265P–Mutated Diffuse Large B-Cell Lymphoma: Analysis of 361 Cases

Abstract

<b>Purpose:</b><i>MYD88</i> mutations, notably the recurrent gain-of-function L265P variant, are a distinguishing feature of activated B-cell like (ABC) diffuse large B-cell lymphoma (DLBCL), leading to constitutive NFκB pathway activation. The aim of this study was to examine the distinct genomic profiles of <i>MYD88</i>-mutant DLBCL, notably according to the presence of the L265P or other non-L265P MYD88 variants.<b>Experimental Design:</b> A cohort of 361 DLBCL cases (94 <i>MYD88</i> mutant and 267 <i>MYD88</i> wild-type) was submitted to next-generation sequencing (NGS) focusing on 34 genes to analyze associated mutations and copy number variations, as well as gene expression profiling, and clinical and prognostic analyses.<b>Results:</b> Importantly, we highlighted different genomic profiles for MYD88 L265P and MYD88 non-L265P-mutant DLBCL, shedding light on their divergent backgrounds. Clustering analysis also segregated subgroups according to associated genetic alterations among patients with the same <i>MYD88</i> mutation. We showed that associated <i>CD79B</i> and MYD88 L265P mutations act synergistically to increase NFκB pathway activation, although the majority of MYD88 L265P-mutant cases harbors downstream NFκB alterations, which can predict BTK inhibitor resistance. Finally, although the MYD88 L265P variant was not an independent prognostic factor in ABC DLBCL, associated <i>CD79B</i> mutations significantly improved the survival of MYD88 L265P-mutant ABC DLBCL in our cohort.<b>Conclusions:</b> This study highlights the relative heterogeneity of <i>MYD88</i>-mutant DLBCL, adding to the field's knowledge of the theranostic importance of <i>MYD88</i> mutations, but also of associated alterations, emphasizing the usefulness of genomic profiling to best stratify patients for targeted therapy. <i>Clin Cancer Res; 23(9); 2232-44. ©2016 AACR</i>.