MYD88 L265P mutation and CDKN2A loss are early mutational events in primary central nervous system diffuse large B-cell lymphomas

Abstract

<p id="d3471725e426"> <div class="list"> <a class="named-anchor" id="d3471725e428"> <!-- named anchor --> </a> <ul class="so-custom-list"> <li id="d3471725e429"> <div class="so-custom-list-content so-ol"> <p class="first" id="d3471725e430"> <i>MYD88</i> L265P mutation and <i>CDKN2A</i> loss are early mutational events in PCNSL. </p> </div> </li> <li id="d3471725e438"> <div class="so-custom-list-content so-ol"> <p class="first" id="d3471725e439">PD-L1 expression was not unregulated in our cohort of PCNSL.</p> </div> </li> </ul> </div> </p><p class="first" id="d3471725e444">The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted <i>MYD88</i> sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified <i>MYD88</i> mutation in 67% (42 of 63) of patients, <i>CDKN2A</i> biallelic loss in 44% (16 of 36), and <i>CD79b</i> mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, <i>CDKN2A</i>), with few areas of amplification. <i>CD79b</i> mutations were associated with improved progression-free and overall survival. We did not identify amplification at the <i>PD-1</i>/ <i>PD-L1</i> loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified <i>MYD88</i> mutation and <i>CDKN2A</i> loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of <i>PD-L1</i> amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions. </p><p id="d3471725e483"> <div class="fig panel" id="absf1"> <a class="named-anchor" id="absf1"> <!-- named anchor --> </a> <div class="figure-container so-text-align-c"> <img alt="" class="figure" src="/document_file/bf97ff9f-7c22-43ff-8287-753286182517/PubMedCentral/image/advances027672absf1"/> </div> <div class="panel-content"/> </div> </p>