Molecular and clinical diversity in primary central nervous system lymphoma - Centre de Recherche en Cancérologie et Immunologie Nantes Angers Access content directly
Journal Articles Annals of Oncology Year : 2023

Molecular and clinical diversity in primary central nervous system lymphoma

Abstract

Background: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. Patients and methods: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we performed a comprehensive multi-omic analysis (whole-exome sequencing, RNA-seq, methyl-seq, and clinical features) in a discovery cohort of 147 fresh-frozen immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. Results: Consensus clustering of multi-omics data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but distinct clinical behavior. The "immune-hot" CS4 group, enriched with mutations increasing the JAK-STAT and NF-κB activity, had the most favorable clinical outcome while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. The CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus PI3K inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and EZH2 inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. Conclusions: The integration of genome-wide data from multi-omics data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.
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Dates and versions

hal-03870175 , version 1 (20-06-2023)

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I. Hernández-Verdin, E. Kirasic, K. Wienand, K. Mokhtari, S. Eimer, et al.. Molecular and clinical diversity in primary central nervous system lymphoma. Annals of Oncology, 2023, 34 (2), pp.186-199. ⟨10.1016/j.annonc.2022.11.002⟩. ⟨hal-03870175⟩
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