Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas

Esteban D Braggio, Scott Van Wier, Juhi Ojha, Ellen McPhail, Yan Asmann, Jan Egan, Jackline Ayres Da Silva, David Schiff, M. Beatriz Lopes, Paul A. Decker, Riccardo Valdez, Raoul Tibes, Bruce Eckloff, Thomas Elmer Witzig, Alexander Keith Stewart, Rafael Fonseca, Brian Patrick O'Neill

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Abstract

Purpose: Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain. Experimental Design: We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing. Results: Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation. Conclusions: In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.

Original languageEnglish (US)
Pages (from-to)3986-3994
Number of pages9
JournalClinical Cancer Research
Volume21
Issue number17
DOIs
StatePublished - Sep 1 2015

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ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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