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

Research output: Contribution to journalArticle

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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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Lymphoma
Central Nervous System
Genome
Lymphoma, Large B-Cell, Diffuse
Exome
Mutation
Comparative Genomic Hybridization
Toll-Like Receptors
B-Cell Lymphoma
Non-Hodgkin's Lymphoma
B-Lymphocytes
Research Design
Lymphocytes
Apoptosis
Genes
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas. / Braggio, Esteban D; Van Wier, Scott; Ojha, Juhi; McPhail, Ellen; Asmann, Yan; Egan, Jan; Da Silva, Jackline Ayres; Schiff, David; Lopes, M. Beatriz; Decker, Paul A.; Valdez, Riccardo; Tibes, Raoul; Eckloff, Bruce; Witzig, Thomas Elmer; Stewart, Alexander Keith; Fonseca, Rafael; O'Neill, Brian Patrick.

In: Clinical Cancer Research, Vol. 21, No. 17, 01.09.2015, p. 3986-3994.

Research output: Contribution to journalArticle

Braggio, Esteban D ; Van Wier, Scott ; Ojha, Juhi ; McPhail, Ellen ; Asmann, Yan ; Egan, Jan ; Da Silva, Jackline Ayres ; Schiff, David ; Lopes, M. Beatriz ; Decker, Paul A. ; Valdez, Riccardo ; Tibes, Raoul ; Eckloff, Bruce ; Witzig, Thomas Elmer ; Stewart, Alexander Keith ; Fonseca, Rafael ; O'Neill, Brian Patrick. / Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas. In: Clinical Cancer Research. 2015 ; Vol. 21, No. 17. pp. 3986-3994.
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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.",
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T1 - Genome-wide analysis uncovers novel recurrent alterations in primary central nervous system lymphomas

AU - Braggio, Esteban D

AU - Van Wier, Scott

AU - Ojha, Juhi

AU - McPhail, Ellen

AU - Asmann, Yan

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 Elmer

AU - Stewart, Alexander Keith

AU - Fonseca, Rafael

AU - O'Neill, Brian Patrick

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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