title: Mutational analysis of primary central nervous system lymphoma.
abstract: Little is known about the genomic basis of primary central nervous system lymphoma (PCNSL) tumorigenesis. To investigate the mutational profile of PCNSL, we analyzed nine paired tumor and germline DNA samples from PCNSL patients by high throughput exome sequencing. Eight genes of interest have been further investigated by focused resequencing in 28 additional PCNSL tumors to better estimate their incidence. Our study identified recurrent somatic mutations in 37 genes, some involved in key signaling pathways such as NFKB, B cell differentiation and cell cycle control. Focused resequencing in the larger cohort revealed high mutation rates for genes already described as mutated in PCNSL such as MYD88 (38%), CD79B (30%), PIM1 (22%) and TBL1XR1 (19%) and for genes not previously reported to be involved in PCNSL tumorigenesis such as ETV6 (16%), IRF4 (14%), IRF2BP2 (11%) and EBF1 (11%). Of note, only 3 somatically acquired SNVs were annotated in the COSMIC database. Our results demonstrate a high genetic heterogeneity of PCNSL and mutational pattern similarities with extracerebral diffuse large B cell lymphomas, particularly of the activated B-cell (ABC) subtype, suggesting shared underlying biological mechanisms. The present study provides new insights into the mutational profile of PCNSL and potential targets for therapeutic strategies.
authors: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013, Paris, France. Institut National de la Santé et de la Recherche Médicale, U 1127, ICM, F-75013, Paris, France. Centre National de la Recherche Scientifique, UMR 7225, ICM, F-75013, Paris, France. ICM, F-75013, Paris, France.
authors: Aurélie
authors: A
authors: Bruno
authors: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013, Paris, France. Institut National de la Santé et de la Recherche Médicale, U 1127, ICM, F-75013, Paris, France. Centre National de la Recherche Scientifique, UMR 7225, ICM, F-75013, Paris, France. ICM, F-75013, Paris, France. Plateforme de Génotypage Séquençage, ICM, F-75013, Paris, France.
authors: Blandine
authors: B
authors: Boisselier
authors: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013, Paris, France. Institut National de la Santé et de la Recherche Médicale, U 1127, ICM, F-75013, Paris, France. Centre National de la Recherche Scientifique, UMR 7225, ICM, F-75013, Paris, France. ICM, F-75013, Paris, France.
authors: Karim
authors: K
authors: Labreche
authors: Plateforme de Génotypage Séquençage, ICM, F-75013, Paris, France. Onconeurothèque, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Yannick
authors: Y
authors: Marie
authors: Centre Hospitalier Universitaire Lariboisière, Assistance Publique-Hôpitaux de Paris, Service d'Anatomopathologie, Paris, France.
authors: Marc
authors: M
authors: Polivka
authors: Hospices Civils de Lyon, Hôpital Neurologique, Bron, France and Université Lyon 1, Institut National de la Santé et de la Recherche Médicale Unité 842, Lyon, France.
authors: Anne
authors: A
authors: Jouvet
authors: Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Service d'anatomopathologie, Bicêtre, France.
authors: Clovis
authors: C
authors: Adam
authors: Centre Hospitalier Universitaire La Timone, Assistance Publique-Hôpitaux de Marseille, Institut National de la Santé et de la Recherche Médicale Unité 911, Centre de Recherches en Oncologie biologique et Onco-pharmacologie, Université de la Méditerranée and Tumorothèque de l'Assistance Publique-Hôpitaux de Marseille (AC 2013-1786), Marseille, France.
authors: Dominique
authors: D
authors: Figarella-Branger
authors: Centre hospitalier Sainte Anne, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Catherine
authors: C
authors: Miquel
authors: Service de Pathologie, CRB Tumorothèque, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France.
authors: Sandrine
authors: S
authors: Eimer
authors: Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France.
authors: Caroline
authors: C
authors: Houillier
authors: Hôpital René Huguenin, Institut Curie, Service d'Hématologie, Saint Cloud, France.
authors: Carole
authors: C
authors: Soussain
authors: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013, Paris, France. Institut National de la Santé et de la Recherche Médicale, U 1127, ICM, F-75013, Paris, France. Centre National de la Recherche Scientifique, UMR 7225, ICM, F-75013, Paris, France. ICM, F-75013, Paris, France. Onconeurothèque, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
authors: Karima
authors: K
authors: Mokhtari
authors: Institut National de la Santé et de la Recherche Médicale Unité 830, Génétique et Biologie des Cancers, Institut Curie, Paris, France.
authors: Romain
authors: R
authors: Daveau
authors: Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013, Paris, France. Institut National de la Santé et de la Recherche Médicale, U 1127, ICM, F-75013, Paris, France. Centre National de la Recherche Scientifique, UMR 7225, ICM, F-75013, Paris, France. ICM, F-75013, Paris, France. Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France.
authors: Khê
authors: K
authors: Hoang-Xuan
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016543:Central Nervous System Neoplasms / Q000235:genetics*; D004252:DNA Mutational Analysis / Q000379:methods; D059472:Exome / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide