title: The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing.
abstract: To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 × followed by mutation verification in 9 PCNSL and validation using Sanger sequencing in 22 PCNSL. We identified a median of 202 (range: 139-251) potentially somatic single nucleotide variants (SNV) and 14 small indels (range: 7-22) with potentially protein-changing features per PCNSL. Mutations affected the B-cell receptor, toll-like receptor, and NF-κB and genes involved in chromatin structure and modifications, cell-cycle regulation, and immune recognition. A median of 22.2% (range: 20.0-24.7%) of somatic SNVs in 9 PCNSL overlaps with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2-12.6%) affects its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to the well-known targets of aberrant SHM (aSHM) (PIM1), our data suggest new targets of aSHM (KLHL14, OSBPL10, and SUSD2). Among the four most frequently mutated genes was ODZ4 showing protein-changing mutations in 4/9 PCNSL. Together with mutations affecting CSMD2, CSMD3, and PTPRD, these findings may suggest that alterations in genes having a role in CNS development may facilitate diffuse large B-cell lymphoma manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Vater
authors.affiliation: Institute of Neuropathology, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Montesinos-Rongen
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schlesner
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Haake
authors.affiliation: Institute of Neuropathology, University of Cologne, Cologne, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Purschke
authors.affiliation: Institute of Neuropathology, University of Cologne, Cologne, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Sprute
authors.affiliation: Institute of Neuropathology, University of Cologne, Cologne, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Mettenmeyer
authors.affiliation: Institute of Neuropathology, University of Cologne, Cologne, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Nazzal
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Nagel
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Gutwein
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Richter
authors.affiliation: Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Buchhalter
authors.affiliation: 1] Cell Networks, University of Heidelberg, Heidelberg, Germany [2] BioQuant, Heidelberg University, Heidelberg, Germany.
authors.forename: R B
authors.initials: RB
authors.lastname: Russell
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: O D
authors.initials: OD
authors.lastname: Wiestler
authors.affiliation: 1] Division of Theoretical Bioinformatics (B080), German Cancer Research Center (DKFZ), Heidelberg, Germany [2] BioQuant, Heidelberg University, Heidelberg, Germany [3] Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB), Heidelberg University, Heidelberg, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Eils
authors.affiliation: Institute of Neuropathology, University of Cologne, Cologne, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Deckert
authors.affiliation: Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Siebert
mesh_terms: D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D056426:Genetic Loci; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D011110:Polymorphism, Genetic; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics; D011987:Receptors, Steroid / Q000235:genetics; D012189:Retrospective Studies; D027041:Somatic Hypermutation, Immunoglobulin; D000098825:Oxysterol Binding Proteins
chemical_list: C477879:CSMD2 protein, human; C477878:CSMD3 protein, human; D007143:Immunoglobulin Heavy Chains; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011987:Receptors, Steroid; C582626:SUSD2 protein, human; C576539:TENM4 protein, human; D000098825:Oxysterol Binding Proteins; C496634:PIM1 protein, human; D051573:Proto-Oncogene Proteins c-pim-1; C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2