The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing

Abstract

To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139-251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7-22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0-24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2-12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.

The Genetics of Nodal Marginal Zone Lymphoma

“…PTPRD encodes a receptor-type protein tyrosine phosphatase that has not been previously described as recurrently mutated in indolent and aggressive lymphomas, with the exception of a few cases of primary central nervous system DLBCL. 52 In NMZL, PTPRD lesions either remove the entire PTPRD gene or damage the tyrosine phosphatase 61 However, NMZL, including PTPRD-affected cases, carry neither Y705-phospho STAT3 nor any other phenotypic or genetic clue of cytokine-signaling deregulation, thus indicating that PTPRD genetic lesions do not act through STAT3 constitutive activation in NMZL. The observation that PTPRD missense substitutions interfere with Y705-phospho STAT3 dephosphorylation by PTPRD in a biochemical assay confirms the deleterious effect of these variants and supports the notion that they are not passenger events.…”

“…By compiling the results of WES, targeted resequencing (Figure 2A), and high-resolution SNP array analysis ( Figure 2B), 41 genes were recurrently affected in $3 of 35 (9%) of NMZL by mutations (n 5 32 genes) or focal CNA (n 5 9 genes), including MLL2 (also known as KMT2D, 34%), PTPRD (20%), NOTCH2 (20%), and KLF2 (17%) ( Figure 3A; supplemental Tables 3 and 4 . Prevalence of nonsynonymous PTPRD mutations among mature B-cell tumors (NMZL, nodal marginal zone lymphoma, data from this study; SMZL, splenic marginal zone lymphoma, data from this study and others 5,6,7,9 ; DLBCL, diffuse large B-cell lymphoma, data from various studies 22,37,45,47 ; BL, Burkitt lymphoma, data from various studies 40,41 ; CLL, chronic lymphocytic leukemia, data from various studies 38,39,44,49 ; MCL, mantle cell lymphoma, data from Beà et al 43 ; PMBCL, primary mediastinal large B-cell lymphoma, data from Gunawardana et al 15 ; FL, follicular lymphoma, data from various studies 37,48 ; MM, multiple myeloma, data from Chapman et al 36 ; WM, Waldenström macroglobulinemia, data from various studies 42,46 ; EMZL, extranodal marginal zone lymphoma, data from this study; PCNSL primary central nervous system lymphoma, data from various studies [52][53][54][55] ).…”

Targetable genetic features of primary testicular and primary central nervous system lymphomas

“…5,[23][24][25] Somatic mutations of MYD88, CD79B, and additional less common targets have been described. 23,24,[26][27][28] PTLs, which are the most common testicular tumors in elderly men, 2 present as focal masses with epididymal and scrotal involvement. At relapse, PTLs often involve additional extranodal sites including the central nervous system (CNS), skin, pleura, and contralateral testis.…”

Comment on “Deficient NLRP3 and AIM2 Inflammasome Function in Autoimmune NZB Mice”

“…Accumulating evidence indicates that BCR biology is central in PCNSL pathogenesis: 1) Several BCR components are targeted by oncogenic activating mutations (6), resulting in tonic BCR signaling; 2) Ig gene sequences generally lack stop codons and do not harbor frameshift mutations, thus, being potentially functional (7); and 3) ongoing somatic hypermutation (SHM) and aberrant SHM are hallmarks of PCNSL (8,9), a process critically depending on a functional BCR.…”