The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing

• Published in: Leukemia Vol. 29; no. 3; pp. 677 - 685
• Main Authors: Vater, I, Montesinos-Rongen, M, Schlesner, M, Haake, A, Purschke, F, Sprute, R, Mettenmeyer, N, Nazzal, I, Nagel, I, Gutwein, J, Richter, J, Buchhalter, I, Russell, R B, Wiestler, O D, Eils, R, Deckert, M, Siebert, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2015; Nature Publishing Group
• Subjects: 45/43; 631/1647/514/1948; 631/208/737; 631/378/2571; 631/67; 631/67/1990/291; 631/67/68; Adult; Aged; B-cell lymphoma; B-cell receptor; Cancer Research; Central nervous system; Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - pathology; Chromatin; Critical Care Medicine; Development and progression; Exome; Exome sequencing; Female; Gene expression; Gene mutations; Genes; Genetic aspects; Genetic Loci; Hematology; High-Throughput Nucleotide Sequencing; Humans; Identification and classification; Immunoglobulin Heavy Chains - genetics; Intensive; Internal Medicine; Lymphocytes B; Lymphoma; Lymphoma, Large B-Cell, Diffuse - genetics; Lymphoma, Large B-Cell, Diffuse - pathology; Lymphomas; Male; Medicine; Medicine & Public Health; Membrane Glycoproteins - genetics; Membrane Proteins - genetics; Methods; Middle Aged; Mutation; Nervous system cancer; NF-κB protein; Nucleotides; Oncology; original-article; Pathogenesis; Polymorphism, Genetic; Proteins; Proto-Oncogene Proteins c-pim-1 - genetics; Receptor-Like Protein Tyrosine Phosphatases, Class 2 - genetics; Receptors, Steroid - genetics; Retrospective Studies; Sequences; Somatic hypermutation; Somatic Hypermutation, Immunoglobulin; Toll-like receptors; Tropism
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2014.264

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.