I Vater, M Montesinos-Rongen, M Schlesner, A Haake, F Purschke, R Sprute, N Mettenmeyer, I Nazzal, I Nagel, J Gutwein, J Richter, I Buchhalter, R B Russell, O D Wiestler, R Eils, M Deckert, R Siebert

To decipher the mutational pattern of primary CNS lymphoma (PCNSL) we performed whole exome-sequencing to a median coverage of 103x 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-, TLR-, and NF-κB-and genes involved in chromatin structure and modifications, cell cycle regulation or immune recognition. A median of 22.2% (range: 20.0%-24.7%) of somatic SNVs in the 9 PCNSL overlap with the RGYW motif targeted by somatic hypermutation (SHM); a median of 7.9% (range: 6.2%-12.6%) affect its hotspot position suggesting a major impact of SHM on PCNSL pathogenesis. In addition to well-known targets of aberrant SHM (PIM1) our data suggest new targets of aberrant SHM (KLHL14, OSBPL10, 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 playing a role in CNS development may facilitate DLBCL manifestation in the CNS. This may point to intriguing mechanisms of CNS tropism in PCNSL.Leukemia accepted article preview online, 05 September 2014. doi:10.1038/leu.2014.264.