Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas

• Published in: Clinical cancer research Vol. 21; no. 17; pp. 3986 - 3994
• Main Authors: Braggio, Esteban, Van Wier, Scott, Ojha, Juhi, McPhail, Ellen, Asmann, Yan W., Egan, Jan, da Silva, Jackline Ayres, Schiff, David, Lopes, M. Beatriz, Decker, Paul A., Valdez, Riccardo, Tibes, Raoul, Eckloff, Bruce, Witzig, Thomas E., Stewart, A. Keith, Fonseca, Rafael, O'Neill, Brian Patrick
• Format: Journal Article
• Language: English
• Published: United States 01.09.2015
• Subjects: Central Nervous System Neoplasms - genetics; Central Nervous System Neoplasms - metabolism; Central Nervous System Neoplasms - mortality; Chromosome Aberrations; Chromosomes, Human, Pair 6; Comparative Genomic Hybridization; DNA Copy Number Variations; Exome; Genetic Variation; Genome-Wide Association Study; High-Throughput Nucleotide Sequencing; Humans; Karyotype; Lymphoma, Non-Hodgkin - genetics; Lymphoma, Non-Hodgkin - metabolism; Lymphoma, Non-Hodgkin - mortality; Mutation; Prognosis
• ISSN: 1078-0432; 1557-3265; 1557-3265
• DOI: 10.1158/1078-0432.CCR-14-2116

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. Clin Cancer Res; 21(17); 3986–94. ©2015 AACR.