Mutational analysis of primary central nervous system lymphoma

// Aurélie Bruno 1,2,3,4 , Blandine Boisselier 1,2,3,4,5 , Karim Labreche 1,2,3,4 , Yannick Marie 5,6 , Marc Polivka 7 , Anne Jouvet 8 , Clovis Adam 9 , Dominique Figarella-Branger 10 , Catherine Miquel 11 , Sandrine Eimer 12 , Caroline Houillier 13 , Carole Soussain 14 , Karima Mokhtari 1,2,3,4,6 Romain Daveau 15 and Khê Hoang-Xuan 1,2,3,4,13 1 Sorbonne Universités, UPMC Univ Paris 06, UM 75, ICM, F-75013 Paris, France 2 Institut National de la Santé et de la Recherche Médicale, U1127, ICM, Paris, F-75013 Paris, France 3 Centre National de la Recherche Scientifique, UMR 7225, ICM, Paris, F-75013 Paris, France 4 ICM, Paris, 75013 France 5 Plateforme de Génotypage Séquençage, ICM, F-75013, Paris, France 6 Onconeurothèque, Groupe Hospitalier Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France 7 Centre Hospitalier Universitaire Lariboisière, Assistance Publique-Hôpitaux de Paris, Service d’Anatomopathologie, Paris, France 8 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 9 Centre Hospitalier Universitaire Bicêtre, Assistance Publique-Hôpitaux de Paris, Service d’anatomopathologie, Bicêtre, France 10 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 11 Centre hospitalier Sainte Anne, Université Paris Descartes, Sorbonne Paris Cité, Paris, France 12 Service de Pathologie, CRB Tumorothèque, Centre Hospitalier Universitaire Bordeaux, Bordeaux, France 13 Assistance Publique-Hôpitaux de Paris, Hôpital de la Pitié-Salpêtrière, Service de Neurologie 2-Mazarin, Paris, France; and the LOC network (INCa) 14 Hôpital René Huguenin, Institut Curie, Service d’Hématologie, Saint Cloud, France; and the LOC network (INCa) 15 Institut National de la Santé et de la Recherche Médicale Unité 830, Génétique et Biologie des Cancers, Institut Curie, Paris, France Correspondence: Khê Hoang-Xuan, email: // Keywords : Primary CNS lymphoma, exome sequencing, somatic mutations, NFΚB, B cell differentiation Received : April 21, 2014 Accepted : June 7, 2014 Published : June 8, 2014 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.