Genome-Wide Analysis Uncovers Novel Recurrent Alterations in Primary Central Nervous System Lymphomas.
Clin Cancer Res, 2015/9/01;21(17):3986-94.
Braggio E[1], Van Wier S[2], Ojha J[2], McPhail E[3], Asmann YW[4], Egan J[2], da Silva JA[5], Schiff D[6], Lopes MB[6], Decker PA[3], Valdez R[2], Tibes R[2], Eckloff B[3], Witzig TE[3], Stewart AK[2], Fonseca R[2], O'Neill BP[3]
Affiliations
PMID: 25991819DOI: 10.1158/1078-0432.CCR-14-2116
Impact factor: 13.801
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.
MeSH terms
Central Nervous System Neoplasms; 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; Mutation; Prognosis
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