Clinicopathologic significance of MYD88 L265P mutation and expression of TLR4 and P-STAT3 in primary central nervous system diffuse large B-cell lymphomas

Tang, Dabei; Su, Wen; Wang, Xiaowei; Chu, Zhong; Zhang, Lei; Zhou, Jin; Zhang, Qingyuan

doi:10.1007/s10014-020-00386-8

Cited by 6 publications

(5 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…2c ). STAT3 has been associated with intracranial spreading and poor survival in PCNSL 69 , 70 , and reports of STAT3 inhibition via small molecules achieve complete tumor regression in vivo for lymphoma cell lines 71 . As STAT3 is not highly mutated or hit by SVs or CNVs, its activation seems—in line with previous reports—induced by extrinsic factors such as infiltrating macrophages/microglial cells 72 , or intrinsic factors such as activation downstream of MYD88 73 .…”

Section: Resultsmentioning

confidence: 99%

The genomic and transcriptional landscape of primary central nervous system lymphoma

et al. 2022

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

The genomic and transcriptional landscape of primary central nervous system lymphoma

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The enrichment analysis in TRRUST revealed 'Regulated by: STAT3' as the most significant term (hypergeometric test, FDR 3.98x10-7; Figure 2 C). STAT3 has been associated with intracranial spreading and poor survival in PCNSL 81,82 , and reports of STAT3 inhibition via small molecules achieve complete tumor regression in vivo for lymphoma cell lines 83 .…”

Section: Driver Mutations In Cnslmentioning

confidence: 99%

The genomic and transcriptional landscape of primary central nervous system lymphoma

Radke

Ishaque

Koll

et al. 2021

Preprint

View full text Add to dashboard Cite

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Despite extensive research, the molecular alterations leading to PCNSL have not been fully elucidated. In order to provide a comprehensive description of the genomic and transcriptional landscape of PCNSL, we here performed whole-genome and transcriptome sequencing and integrative analysis of 51 lymphomas presenting in the CNS, including 42 EBV-negative PCNSL, 6 secondary CNS lymphomas (SCNSL) and 3 EBV+ CNSL and matched controls. The results were compared to an independent validation cohort of 31 FFPE CNSL specimens (PCNSL, n = 19; SCNSL, n = 9; EBV+ CNSL, n = 3) as well as 39 FL and 36 systemic DLBCL cases outside the CNS. Somatic genomic alterations in PCNSL mainly affect the JAK-STAT, NFkB, and B-cell receptor signaling pathways, with hallmark recurrent mutations including MYD88 L265P (67%) and CD79B (63%), CDKN2A deletions (83%) and also non-coding RNA genes such as MALAT1 (70%), NEAT (60%), and MIR142 (80%). Kataegis events, which affected 15 of 50 identified driver genes and 21 of the top 50 mutated ncRNAs, played a decisive role in shaping the mutational repertoire of PCNSL. Compared to systemic DLBCL, PCNSLs exhibited significantly more focal deletions in 6p21 targeting the HLA-D locus that encodes for MHC class II molecules as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis (SBS1, ID1 and ID2) were significantly enriched in PCNSL (SBS1: p = 0.0027, ID1/ID2: p < 1x10-4). Furthermore, TERT gene expression was significantly higher in PCNSL compared to ABC-DLBCL (p = 0.027). Although PCNSL share many genetic alterations with systemic ABC-DLBCL in the same signaling pathways, transcriptome analysis clearly distinguished both into distinct molecular subtypes. EBV+ CNSL cases may be distinguished by lack of recurrent mutational hotspots apart from IG and HLA-DRB loci.

show abstract

“…STAT3 is an important transcription factor and enhanced phosphorylation of STAT is present in late stages of inflammation and immune response, which can promote the expression of immunosuppressive molecules and suppress immune response. It has been shown that elevated STAT3 expression and enhanced phosphorylation in tumour cells of PCNSL can suppress the immune response of tumour cells ( Ruggieri et al, 2017 ; Tang et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Molecular characteristics of immunocytes infiltration in primary central nervous system lymphoma

Zhang

Sun²,

Lu³

et al. 2022

Front. Genet.

View full text Add to dashboard Cite

Background: Primary central nervous system lymphoma (PCNSL) is a rare B-cell lymphoma of central nervous system, which is often found in immunocompromised patients. The common clinical treatment of PCNSL is methotrexate (MTX) and whole brain radiation therapy. With the development of tumour immunology research, the tumour microenvironment of PCNSL is characterised by abnormal expression of different immune signature molecules and patients with PCNSL may benefit from tumour immunotherapy.Methods: In our research, RNA-seq data from 82 PCNSL patients were collated by mining the microarray data from the GEO database. All samples were classified into three types related to tumour immune response by the Cibersort algorithm and consistent clustering. Differential analysis of genes was used to uncover 2 sets of differential genes associated with tumour immunity. The ICI scores of each sample were obtained by PCA algorithm, and the relationship between ICI scores and immune checkpoint expression, immunotherapy and drug sensitivity was investigated. Genes associated with ICI scores and their functional characteristics were investigated by WGCNA analysis and PPI analysis, based on the ICI scores of each sample.Results: The tumour microenvironment in PCNSL has a greater relationship with the tumour immune response. ICI scores obtained from 375 differential genes were associated with multiple immune responses in PCNSL. PCNSL patients with higher ICI scores had a better tumour microenvironment and were sensitive to immunotherapy and some small molecule drug. This study also identified 64 genes associated with ICI scores, which may serve as important therapeutic and prognostic targets for PCNSL.Conclusion: The presence of multiple immunosuppressive responses in the tumour microenvironment of PCNSL which suggested that improving the immune function of PCNSL patients through immunotherapy and targeted therapies can be an effective treatment for PCNSL. And the ICI score and associated genes may also provide a better predictor of the clinical use of immunotherapy.

show abstract

Clinicopathologic significance of MYD88 L265P mutation and expression of TLR4 and P-STAT3 in primary central nervous system diffuse large B-cell lymphomas

Cited by 6 publications

References 31 publications

The genomic and transcriptional landscape of primary central nervous system lymphoma

The genomic and transcriptional landscape of primary central nervous system lymphoma

The genomic and transcriptional landscape of primary central nervous system lymphoma

Molecular characteristics of immunocytes infiltration in primary central nervous system lymphoma

Contact Info

Product

Resources

About