<i>MYD88</i> mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis

Abstract

The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of <i>MYC/BCL2/BCL6</i> as drivers of lymphomagenesis. A subset of DLBCL, however, is characterized by activating mutations in <i>MYD88/CD79B</i> We investigated whether <i>MYD88/CD79B</i> mutations could improve the classification and prognostication of DLBCL. In 250 primary DLBCL, <i>MYD88/CD79B</i> mutations were identified by allele-specific polymerase chain reaction or next-generation-sequencing, <i>MYC/BCL2/BCL6</i> rearrangements were analyzed by fluorescence <i>in situ</i> hybridization, and EBV was studied by EBV-encoded RNA <i>in situ</i> hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. <i>MYD88</i> and <i>CD79B</i> mutations were identified in 29.6% and 12.3%, <i>MYC, BCL2</i>, and <i>BCL6</i> rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and <i>MYD88/CD79B</i> mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. <i>MYD88</i>-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type <i>MYD88</i> DLBCL (log-rank; <i>P</i>=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases carrying ≥1 aberrancy (log-rank; <i>P</i>=0.010). <i>MYD88</i> mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic performance of the IPI. This study demonstrates the clinical utility of defining <i>MYD88</i>-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of <i>MYD88</i> in routine diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies.