A genome-wide association study identifies susceptibility loci for primary central nervous system lymphoma at 6p25.3 and 3p22.1: a LOC Network study
Karim Labreche
(1, 2)
,
Mailys Daniau
(2, 3)
,
Amit Sud
(1)
,
Philip J Law
(1)
,
Louis Royer-Perron
(2, 4)
,
Amy Holroyd
(1)
,
Peter Broderick
(1)
,
Molly Went
(1)
,
Marion Benazra
(2, 3)
,
Guido Ahle
(5)
,
Pierre Soubeyran
(6, 7)
,
Luc Taillandier
(8, 9)
,
Olivier Chinot
(10, 11)
,
Olivier Casasnovas
(12)
,
Jacques-Olivier Bay
(13)
,
Fabrice Jardin
(14, 15)
,
Lucie Oberic
(16)
,
Michel Fabbro
(17)
,
Gandhi Damaj
(18)
,
Annie Brion
(19)
,
Karima Mokhtari
(2, 4, 20)
,
Cathy Philippe
(21)
,
Marc Sanson
(4, 2, 20)
,
Caroline Houillier
(2)
,
Carole Soussain
(22)
,
Khê Hoang-Xuan
(2, 4)
,
Richard Houlston
(1)
,
Agusti Alentorn
(2, 4)
1
The institute of cancer research [London]
2 ICM - Institut du Cerveau = Paris Brain Institute
3 Plateforme iGenSeq [ICM Paris]
4 CHU Pitié-Salpêtrière [AP-HP]
5 Service de Neurologie [Hôpitaux Civils de Colmar]
6 Institut Bergonié [Bordeaux]
7 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
8 CRAN - Centre de Recherche en Automatique de Nancy
9 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
10 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
11 TIMONE - Hôpital de la Timone [CHU - APHM]
12 Service d'Hématologie Clinique (CHU de Dijon)
13 CHU Clermont-Ferrand
14 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
15 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
16 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
17 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
18 Laboratoire d'Hématologie [CHU Amiens]
19 Service d'hématologie
20 OncoNeuroTek [ICM Paris]
21 IRCM - Institut de Radiobiologie Cellulaire et Moléculaire
22 Hôpital René Huguenin [Saint-Cloud]
2 ICM - Institut du Cerveau = Paris Brain Institute
3 Plateforme iGenSeq [ICM Paris]
4 CHU Pitié-Salpêtrière [AP-HP]
5 Service de Neurologie [Hôpitaux Civils de Colmar]
6 Institut Bergonié [Bordeaux]
7 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
8 CRAN - Centre de Recherche en Automatique de Nancy
9 CHRU Nancy - Centre Hospitalier Régional Universitaire de Nancy
10 CRO2 - Centre de Recherches en Oncologie biologique et Oncopharmacologie
11 TIMONE - Hôpital de la Timone [CHU - APHM]
12 Service d'Hématologie Clinique (CHU de Dijon)
13 CHU Clermont-Ferrand
14 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
15 CLCC Henri Becquerel - Centre de Lutte Contre le Cancer Henri Becquerel Normandie Rouen
16 IUCT Oncopole - UMR 1037 - Institut Universitaire du Cancer de Toulouse - Oncopole
17 ICM - UNICANCER - Institut régional du Cancer Montpellier Val d'Aurelle
18 Laboratoire d'Hématologie [CHU Amiens]
19 Service d'hématologie
20 OncoNeuroTek [ICM Paris]
21 IRCM - Institut de Radiobiologie Cellulaire et Moléculaire
22 Hôpital René Huguenin [Saint-Cloud]
Karim Labreche
- Fonction : Auteur
- PersonId : 748822
- IdHAL : karim-labreche
- ORCID : 0000-0002-3164-9406
Pierre Soubeyran
- Fonction : Auteur
- PersonId : 752156
- IdHAL : plsoubhal2022
- ORCID : 0000-0003-3244-7299
- IdRef : 060718668
Olivier Chinot
- Fonction : Auteur
- PersonId : 172185
- IdHAL : olivier-chinot
- IdRef : 034791205
Marc Sanson
- Fonction : Auteur
- PersonId : 900672
Agusti Alentorn
- Fonction : Auteur
- PersonId : 1157071
- IdHAL : agusti-alentorn
Résumé
Background: Primary central nervous system lymphoma (PCNSL) is a rare form of extra-nodal non-Hodgkin lymphoma. PCNSL is a distinct subtype of non-Hodgkin lymphoma, with over 95% of tumors belonging to the diffuse large B-cell lymphoma (DLBCL) group. We have conducted a genome-wide association study (GWAS) on immunocompetent patients to address the possibility that common genetic variants influence the risk of developing PCNSL.
Methods: We performed a meta-analysis of 2 new GWASs of PCNSL totaling 475 cases and 1134 controls of European ancestry. To increase genomic resolution, we imputed >10 million single nucleotide polymorphisms using the 1000 Genomes Project combined with UK10K as reference. In addition we performed a transcription factor binding disruption analysis and investigated the patterns of local chromatin by Capture Hi-C data.
Results: We identified independent risk loci at 3p22.1 (rs41289586, ANO10, P = 2.17 × 10-8) and 6p25.3 near EXOC2 (rs116446171, P = 1.95 x 10-13). In contrast, the lack of an association between rs41289586 and DLBCL suggests distinct germline predisposition to PCNSL and DLBCL. We found looping chromatin interactions between noncoding regions at 6p25.3 (rs11646171) with the IRF4 promoter and at 8q24.21 (rs13254990) with the MYC promoter, both genes with strong relevance to B-cell tumorigenesis.
Conclusion: To our knowledge this is the first study providing insight into the genetic predisposition to PCNSL. Our findings represent an important step in defining the contribution of common genetic variation to the risk of developing PCNSL.