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

Leukemia. 2015 Mar;29(3):677-85. doi: 10.1038/leu.2014.264. Epub 2014 Sep 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Central Nervous System Neoplasms / genetics*
  • Central Nervous System Neoplasms / pathology
  • Exome*
  • Female
  • Genetic Loci
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoglobulin Heavy Chains / genetics
  • Lymphoma, Large B-Cell, Diffuse / genetics*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Male
  • Membrane Glycoproteins / genetics
  • Membrane Proteins / genetics
  • Middle Aged
  • Polymorphism, Genetic*
  • Proto-Oncogene Proteins c-pim-1 / genetics
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2 / genetics
  • Receptors, Steroid / genetics
  • Retrospective Studies
  • Somatic Hypermutation, Immunoglobulin*


  • CSMD2 protein, human
  • CSMD3 protein, human
  • Immunoglobulin Heavy Chains
  • Membrane Glycoproteins
  • Membrane Proteins
  • Receptors, Steroid
  • SUSD2 protein, human
  • TENM4 protein, human
  • oxysterol binding protein
  • PIM1 protein, human
  • Proto-Oncogene Proteins c-pim-1
  • PTPRD protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 2