TY - JOUR
T1 - Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas
AU - Braggio, Esteban
AU - Van Wier, Scott
AU - Ojha, Juhi
AU - McPhail, Ellen
AU - Asmann, Yan W.
AU - Egan, Jan
AU - Da Silva, Jackline Ayres
AU - Schiff, David
AU - Lopes, M. Beatriz
AU - Decker, Paul A.
AU - Valdez, Riccardo
AU - Tibes, Raoul
AU - Eckloff, Bruce
AU - Witzig, Thomas E.
AU - Stewart, A. Keith
AU - Fonseca, Rafael
AU - O'Neill, Brian Patrick
N1 - Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2015/9/1
Y1 - 2015/9/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-14-2116
DO - 10.1158/1078-0432.CCR-14-2116
M3 - Article
C2 - 25991819
AN - SCOPUS:84939563989
SN - 1078-0432
VL - 21
SP - 3986
EP - 3994
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 17
ER -