Molecular and clinical diversity in primary central nervous system lymphoma

I. Hernández-Verdin (1) , E. Kirasic (1) , K. Wienand (2, 3, 4) , K. Mokhtari (1, 5) , S. Eimer (6) , H. Loiseau (7, 8) , A. Rousseau (9, 10) , J. Paillassa (10) , G. Ahle (11) , F. Lerintiu (12) , E. Uro-Coste (13, 14) , L. Oberic (14) , D. Figarella-Branger (15, 16) , O. Chinot (15, 16) , G. Gauchotte (17, 18) , L. Taillandier (18) , J.-P. Marolleau (19, 20) , M. Polivka (21) , C. Adam (22) , R. Ursu (23, 24) , A. Schmitt (25) , N. Barillot (1) , L. Nichelli (26, 5) , F. Lozano-Sánchez (26, 5) , M.-J. Ibañez-Juliá (27) , M. Peyre (1, 5) , B. Mathon (1, 5) , Y. Abada (5, 26) , F. Charlotte (26, 5) , F. Davi (5, 26) , C. Stewart (28) , A. de Reyniès (29) , S. Choquet (5, 26) , C. Soussain (30) , C. Houillier (5, 26) , B. Chapuy (2, 4) , K. Hoang-Xuan (1, 5) , A. Alentorn (1, 5)

1 ICM - Institut du Cerveau = Paris Brain Institute
2 UMG - University Medical Center Göttingen
3 Freie Universität Berlin
4 Charité - UniversitätsMedizin = Charité - University Hospital [Berlin]
5 CHU Pitié-Salpêtrière [AP-HP]
6 Service de pathologie [Bordeaux]
7 CHU Bordeaux [Bordeaux]
8 IMOTION - Imagerie moléculaire et thérapies innovantes en oncologie
9 CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
10 CHU Angers - Centre Hospitalier Universitaire d'Angers
11 Service de Neurologie [Hôpitaux Civils de Colmar]
12 Hôpitaux Civils de Colmar
13 CRCT - Centre de Recherches en Cancérologie de Toulouse
14 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
15 TIMONE - Hôpital de la Timone [CHU - APHM]
16 INP - Institut de neurophysiopathologie
17 NGERE - Nutrition-Génétique et Exposition aux Risques Environnementaux
18 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
19 CHU Amiens-Picardie
20 HEMATIM - HEMATIM - Hématopoïèse et immunologie - UR UPJV 4666
21 Hôpital Lariboisière-Fernand-Widal [APHP]
22 AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
23 UPD7 - Université Paris Diderot - Paris 7
24 AP-HP - Hopital Saint-Louis [AP-HP]
25 Institut Bergonié [Bordeaux]
26 SU - Sorbonne Université
27 Centre Hospitalier Saint Jean de Perpignan
28 BROAD INSTITUTE - Broad Institute of MIT and Harvard
29 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
30 ICSC - Institut Curie - Saint Cloud

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.

Mots clés: PCNSL; microenvironment; multi-omics; tumor heterogeneity

Domaines: Médecine humaine et pathologie

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⟩