Universität zu Köln

Vater, I., Montesinos-Rongen, M., Schlesners, M., Haakel, 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. and Siebert, R. (2015). The mutational pattern of primary lymphoma of the central nervous system determined by whole-exome sequencing. Leukemia, 29 (3). S. 677 - 686. LONDON: NATURE PUBLISHING GROUP. ISSN 1476-5551

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Abstract

To decipher the mutational pattern of primary CNS lymphoma (PCNSL), we performed whole-exome sequencing to a median coverage of 103 x 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-kappa B 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Vater, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Montesinos-Rongen, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlesners, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Haakel, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Purschke, F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sprute, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mettenmeyer, N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nazzal, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nagel, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gutwein, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Richter, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Buchhalter, I. UNSPECIFIED UNSPECIFIED UNSPECIFIED Russell, R. B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wiestler, O. D. UNSPECIFIED UNSPECIFIED UNSPECIFIED Eils, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Deckert, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Siebert, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-406981
DOI:	10.1038/leu.2014.264
Journal or Publication Title:	Leukemia
Volume:	29
Number:	3
Page Range:	S. 677 - 686
Date:	2015
Publisher:	NATURE PUBLISHING GROUP
Place of Publication:	LONDON
ISSN:	1476-5551
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language B-CELL LYMPHOMA; PRIMARY CNS LYMPHOMA; IMMUNE-PRIVILEGED SITES; CLASS-II GENES; EXPRESSION; BCL6; GENOME; MYC; REARRANGEMENTS; HYPERMUTATION Multiple languages Oncology; Hematology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/40698