Molecular and clinical diversity in primary central nervous system lymphoma

• DOI: 10.1016/j.annonc.2022.11.002
• Publication Date: 2022-11-17T08:36:06Z
• Authors: I. Hernández-Verdin; E. Kirasic; K. Wienand; K. Mokhtari; S. Eimer; H. Loiseau; A. Rousseau; J. Paillassa; G. Ahle; F. Lerintiu; E. Uro-Coste; L. Oberic; D. Figarella-Branger; O. Chinot; G. Gauchotte; L. Taillandier; J.-P. Marolleau; M. Polivka; C. Adam; R. Ursu; A. Schmitt; N. Barillot; L. Nichelli; F. Lozano-Sánchez; M.-J. Ibañez-Juliá; M. Peyre; B. Mathon; Y. Abada; F. Charlotte; F. Davi; C. Stewart; A. de Reyniès; S. Choquet; C. Soussain; C. Houillier; B. Chapuy; K. Hoang-Xuan; A. Alentorn
• Keywords: Central Nervous System; 0303 health sciences; [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology; Polycomb Repressive Complex 2; multi-omics; microenvironment; 3. Good health; Central Nervous System Neoplasms; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; tumor heterogeneity; Mutation; Humans; Lymphoma, Large B-Cell, Diffuse; PCNSL

Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell presenting with variable response rates probably to underlying molecular heterogeneity.To identify characterize PCNSL heterogeneity facilitate clinical translation, we carried out comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation features] in discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs validation formalin-fixed, paraffin-embedded (FFPE) 93 RNA-seq clinico-radiological data.Consensus clustering data uncovered concordant classification four robust, non-overlapping, prognostically significant clusters (CS). The CS1 CS2 groups presented an immune-cold hypermethylated profile but behavior. 'immune-hot' CS4 group, enriched mutations increasing the Janus kinase (JAK)-signal transducer activator transcription (STAT) nuclear factor-κB activity, had most favorable outcome, while heterogeneous-immune CS3 group worse prognosis due its association meningeal infiltration HIST1H1E mutations. was characterized by high Polycomb repressive complex 2 activity CDKN2A/B loss leading higher proliferation activity. Integrated on proposed targets suggests potential use immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) CS1, lenalidomide/demethylating drugs CS2, enhancer zeste polycomb subunit (EZH2) CS3. We developed algorithm subtypes using from either FFPE or FF tissue.The integration genome-wide revealed patterns distinctive prognostic impact that provides basis future stratification subtype-based targeted interventions.