Data from Large B-cell Lymphomas of Immune-Privileged Sites Relapse via Parallel Clonal Evolution from a Common Progenitor B Cell

Abstract

<div>Abstract<p>Large B-cell lymphoma of immune-privileged sites (LBCL-IP) arise in immune sanctuaries including the testis and central nervous system (CNS). After initially reaching complete response, relapses occur in almost 50% of patients, typically at other immune-privileged sites. Resolution of the clonal relationships and evolutionary patterns of LBCL-IP is required to understand the unique clinical behavior. We collected a unique set of 33 primary–relapse LBCL-IP sample pairs and performed next-generation sequencing for copy number, mutation, translocation, and immunoglobulin clonality analysis. All LBCL-IP sample pairs were clonally related, and both tumors developed from a common progenitor cell (CPC) with <i>MYD88</i> and <i>TBL1XR1</i> mutations and/or <i>BCL6</i> translocations in 30/33 cases, indicating that these are early genetic events. This was succeeded by intermediate genetic events including shared, as well as unique alterations in targets of aberrant somatic hypermutation (aSHM), <i>CD79B</i> mutations, and 9p21.3/<i>CDKN2A</i> loss. Genetic alterations in genes involved in immune escape (<i>HLA</i>, <i>CD274/PDCD1LG2</i>) were predominantly unique in primary and relapse samples and thus considered late genetic events. Together, this study indicates that primary and relapsed LBCL-IP follow an early parallel evolutionary pattern where the CPC contains genetic alterations that support prolonged survival/proliferation and retention in a memory B-cell state, followed by germinal center reentry, aSHM and immune escape.</p>Significance:<p>Genomic analyses reveal that primary and relapse LBCL-IP originate from a common progenitor cell with a small set of genetic alterations, followed by extensive parallel diversification, elucidating the clonal evolution of LBCL-IP.</p></div>