Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

Abstract

Purpose Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the CNS. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental design We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results Biallelic inactivation of TOX and PRKCD were recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. Additionally, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11 and translocations IgH-BCL6. Overall, BCR/TLR/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.

The Genetics of Nodal Marginal Zone Lymphoma

“…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] ).…”

Genomic Profiling of a Large Set of Diverse Pediatric Cancers Identifies Known and Novel Mutations across Tumor Spectra

“…Germline variants in this gene are implicated in hereditary pancreatitis and an increased risk of pancreatic ductal adenocarcinoma (41). The G191R alteration occurs within the peptidase domain and has been reported in a single primary central nervous system lymphoma (42). Notably, no other known alterations were found in two of the four samples harboring the PRSS1 mutation (Supplementary Fig.…”

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.…”