Molecular Subtypes and Genomic Profile of Primary Central Nervous System Lymphoma

Abstract

Primary central nervous system lymphomas (PCNSL) are aggressive non-Hodgkin lymphomas affecting the central nervous system (CNS). Although immunophenotyping studies suggested an uniform activated B-cell (ABC) origin, more recently a spectrum of ABC and germinal center B-cell (GC) cases has been proposed, with the molecular subtypes of PCNSL still being a matter of debate. With the emergence of novel therapies demonstrating different efficacy between the ABC and GC patient groups, precise assignment of molecular subtype is becoming indispensable. To determine the molecular subtype of 77 PCNSL and 17 secondary CNS lymphoma patients, we used the NanoString Lymphoma Subtyping Test (LST), a gene expression-based assay representing a more accurate technique of subtyping compared with standard immunohistochemical (IHC) algorithms. Mutational landscapes of 14 target genes were determined using ultra-deep next-generation sequencing. Using the LST-assay, a significantly lower proportion (80% vs 95%) of PCNSL cases displayed ABC phenotype compared with the IHC-based characterization. The most frequently mutated genes included MYD88, PIM1, and KMT2D. In summary, we successfully applied the LST-assay for molecular classification of PCNSL, reporting higher proportion of cases with GC phenotype compared with IHC analyses, leading to a more precise patient stratification potentially applicable in the diagnostic algorithm of PCNSL.

Whole-Genome/Exome Sequencing Uncovers Mutations and Copy Number Variations in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System

“…When taking into account these four cohorts, mutations in 226 genes were exclusively found in “our cohort” ( Supplementary Figure S1 ). Two genes, PIM1 , the cell cycle/adhesion gene ( Bodor et al, 2020 ; Ou et al, 2020 ), and MYD88 , that were detected in our cohort have also been reported in multiple studies, including Vater et al (2015) , Bruno et al (2014) , Fukumura et al (2016) , and Takashima et al (2018) . Among these 226 genes identified exclusively in our cohort, 28 genes were detected in at least 4 cases, including CXCR4, RECQL, MSH3, RAD51B, RBM10, MAP3K13, KDM5A, EPHA5, RHOA, KMT2B, GNA13, DROSHA, EIF4E, PLK2, LYN, ZFP36L1, CHD2, ITPKB, SF3B1, RAD54L, SHOC2, PGR, POLE, ROBO2, HIST1H2BD, CDKN2A, HIST1H1C, and KMT2C .…”

EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity

“…EBV 2 HIV 2 PCNSL was enriched in previously identified mutations. [3][4][5][6][7][8][9][10] Mutations at high frequency ($20%) include MYD88, CD79B, PIM1, KMT2D, TBL1XR1, TOX, and PRDM1. These involve BCR-NF-kB signaling, epigenetic regulation, cell cycle/adhesion, and B-cell differentiation.…”

“…8 Among other highfrequency mutations is the cell-cycle/adhesion gene PIM1. 9,10 Rarely, PCNSL occurs with immunosuppression (eg, posttransplant lymphoproliferative disorder [PTLD] or HIV [AIDS-related PCNSL]). 11 Although no accurate figures exist, it has been estimated that overall PCNSL after immunosuppression accounts for ,10% of PCNSL cases (,0.1% of NHL).…”

The genomic and transcriptional landscape of primary central nervous system lymphoma

“…By gene expression profiling, the tumor cells are most closely related to late germinal center (exit) B-cells 11 . Pathomechanistic genomic alterations involving Toll-like-and B-cell receptor (TLR, BCR) signaling pathways have been identified in previous studies revealing a very high frequency of somatic nonsynonymous mutations in genes such as MYD88, CARD11, and CD79B [12][13][14][15][16] . Additionally, often homozygous HLA class II 17,18 and CDKN2A loss, recurrent BCL6 translocations 19,20 and structural variants at chromosome band 9p24.1 (affecting CD274/PD-L1 and PDCD1LG2/PD-L2) 21 as well as TBL1XR1 variants 22 have been repeatedly described in PCNSL 23,24 .…”