The genomic and transcriptional landscape of primary central nervous system lymphoma

Abstract

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations.

Auxin Coordinates Achene and Receptacle Development During Fruit Initiation in Fragaria vesca

“…When both read pairs aligned uniquely, they were used toward gene read counts. Then, featureCounts v2.0.1 (Yang et al, 2014 ; Radke et al, 2022 ) was used to count the non-strand-specific reads for gene exon features based on the Genome v4.0.a2 gene model. Gene functional annotation was performed based on Fragaria_vesca_v4.0.a2 protein and Fragaria_vesca_v4.0.a2 transcript annotation provided in Rosaceae website ( https://www.rosaceae.org/species/fragaria/all ).…”

Prognostic factors in primary central nervous system lymphoma

“…Biologically, PCNSL correspond to at mature B-cell germinal centre exit stages, with several pathways deregulated by genetic alterations resulting in constitutive NF-kB activity driven by mutations in genes of the JAK-STAT, B-cell receptor (BCR) and the toll-like receptor (TLR) signalling pathways [90 ▪ ]. Recently, PCNSL-gene profiling has been assimilated to a new molecular subset of DLBCL named ‘MCD’ / Cluster 5 (C5) DLBCL for which a derivation from long-lived memory-B cells has been proposed.…”

“…Recently, PCNSL-gene profiling has been assimilated to a new molecular subset of DLBCL named ‘MCD’ / Cluster 5 (C5) DLBCL for which a derivation from long-lived memory-B cells has been proposed. This subtype is characterized by the presence of frequent MYD88 L265P , CD79B , PIM1 , CARD11 et TBL1XR1 , BTG2 mutations, IgH-BCL6 translocations, copy gains of 3q12.3, 9p24.1 (PD-L1/PD-L2) and copy losses of 6p21–22 (HLA locus), 6q21 and 9p21.3 ( CDKN2A homozygous deletion) [90 ▪ ,91–93,94]. Some molecular genetic alterations have been reported to have individually prognostic impact in PCNSL by several independent studies, including CDKN2A homozygous deletions present in up to 80% of cases [95,96] and chromosome 6q21 present in 40% of cases [96–98], while BCL6 alteration or expression has given conflicting results in PCNSL [26,99,100].…”

CNS Lymphoma: Clinical Pearls and Management Considerations

“…This is a primary reason for limiting steroids prior to biopsy to enhance diagnostic yield. Genetic analysis has recently transitioned to the important role of the JAK-STAT pathway [44]. Particular emphasis has been placed on evaluation of Jak3 and Stat3 and the associated proinflammatory cascade [45].…”

“…Particular emphasis has been placed on evaluation of Jak3 and Stat3 and the associated proinflammatory cascade [45]. Other important pathways identified and actively being investigated include NFkB DNA modification, CDKN2A deletions, B-cell receptor signaling, and mutations in MYD88, L265P and CD79B [44].…”