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
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
Résumé
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.