GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

Abstract

Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin's B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. these results suggest that the GSeA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances. Primary central nervous system lymphoma (PCNSL) is a rare subtype of cerebral malignant non-Hodgkin's B-cell lymphoma with a median overall survival (OS) of approximately four years, which accounts for 3% of all primary brain tumors and 1% of non-Hodgkin's lymphomas (NHLs) in adults 1,2. Methotrexate (MTX) is an antifolate that inhibits dihydrofolate (DHF) reductase (DHFR) activity in purine and thymidine syntheses and regulates the expression of glucocorticoid receptors α and β in human blood cells in vitro 3,4. High-dose MTX (HD-MTX) is used as a first-line treatment in PCNSL 5. Second-line treatments are also required for 10-35% of patients with refractory diseases and for another 35-60% or more who have relapse-acquired MTX resistances 6. Thus, almost PCNSLs recur with MTX resistances despite standard treatments 7. MTX is an antifolate that inhibits DNA synthesis 4. DHFR converts DHF to tetrahydrofolate (THF), a basic form of reduced folate coenzymes 8. MTX resistances are acquired through alternative intrinsic mechanisms in malignant cells, which include decreased drug transport due to mutations and reduced transcription activity of folate carrier genes, dysregulated DHFR activity and affinity, and decreased polyglutamination of MTX due to decreased folylpolyglutamate synthetase (FPGS) activity and increased γ-glutamyl hydrolase (GGH) activity 9-11. MTX exposure induces the activity of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), serine hydroxymethyltransferase 1 (SHMT1), 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocystein...

COVID-19 Specific Immune Markers Revealed by Single Cell Phenotypic Profiling

“…Alternative gene signatures were also observed in HLA-DR high and HLA-DR low monocytes in COVID-19 patients. Interestingly, gene set enrichment analysis (GSEA) [ 41 , 42 ] identified an enrichment of “inflammatory response” and “IL2/STAT5 signaling” reactome [ 43 , 44 ] gene sets in HLA-DR high monocytes from healthy donors ( Figure 5 C), which release proinflammatory cytokines under IL2 stimulation [ 45 ]. Additionally, the “adaptive immune system” and “IL1 family signaling” reactome gene sets, which mediate the inflammation in response to several stimuli, including viruses [ 46 ], were enriched in HLA-DR low control monocytes ( Figure 5 E).…”

Prognostic signature of lung adenocarcinoma based on stem cell-related genes

“…In the KEGG pathways, five pathways were positively associated with the low-risk group, such as ECM receptor interaction, focal adhesion, glycosphingogolipid biosynthesis latco, and neolatco series, pentose phosphate pathway, and p53 signaling pathway. While five pathways were negatively related to the low-risk group, like JAK start signaling pathway, primary immunodeficiency, VEGF signaling pathway, and intestinal immune network for IGA production 20 (Fig. 5 A).…”

Stem Cell-Related Prognostic Signature for Lung Adenocarcinoma

“…While there were ve pathways were negatively related to the low-risk group, like JAK start signaling pathway, primary immunode ciency, VEGF signaling pathway, B cell receptor signaling pathway and T cell receptor signaling pathway (Fig. 5B) [22].…”