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Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition
BACKGROUND: B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort o...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847534/ https://www.ncbi.nlm.nih.gov/pubmed/36342081 http://dx.doi.org/10.1093/oncolo/oyac190 |
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author | Severson, Eric A Haberberger, James Hemmerich, Amanda Huang, Richard S P Edgerly, Claire Schiavone, Kelsie Najafian, Adib Hiemenz, Matthew Lechpammer, Mirna Vergilio, Jo-Anne Lesser, Glenn Strowd, Roy Elvin, Julia Ross, Jeffrey S Hegde, Priti Alexander, Brian Singer, Samuel Ramkissoon, Shakti |
author_facet | Severson, Eric A Haberberger, James Hemmerich, Amanda Huang, Richard S P Edgerly, Claire Schiavone, Kelsie Najafian, Adib Hiemenz, Matthew Lechpammer, Mirna Vergilio, Jo-Anne Lesser, Glenn Strowd, Roy Elvin, Julia Ross, Jeffrey S Hegde, Priti Alexander, Brian Singer, Samuel Ramkissoon, Shakti |
author_sort | Severson, Eric A |
collection | PubMed |
description | BACKGROUND: B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL. MATERIALS AND METHODS: Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. RESULTS: Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted. CONCLUSION: CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma. |
format | Online Article Text |
id | pubmed-9847534 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-98475342023-01-20 Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition Severson, Eric A Haberberger, James Hemmerich, Amanda Huang, Richard S P Edgerly, Claire Schiavone, Kelsie Najafian, Adib Hiemenz, Matthew Lechpammer, Mirna Vergilio, Jo-Anne Lesser, Glenn Strowd, Roy Elvin, Julia Ross, Jeffrey S Hegde, Priti Alexander, Brian Singer, Samuel Ramkissoon, Shakti Oncologist Hematologic Malignancies BACKGROUND: B-cell primary central nervous system (CNS) lymphoma (PCL) is diffuse large B-cell lymphoma (DLBCL) confined to the CNS. Less than 50% of patients with PCL achieve complete remission with current therapies. We describe the findings from comprehensive genomic profiling (CGP) of a cohort of 69 patients with PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL to highlight their differences and characterize the PCL cohort. In addition, we highlight the differences in frequency of germinal center B-cell like (GCB) and non-GCB subtypes and molecular subtypes, particularly MCD and EZH subtypes, between PCL and DLBCL. MATERIALS AND METHODS: Sixty-nine cases of B-cell PCL, 36 cases of secondary CNS lymphoma (SCL), and 969 cases of DLBCL were evaluated by CGP of 405 genes via DNAseq and 265 genes via RNAseq for fusions (FoundationOne Heme). Tumor mutational burden (TMB) was calculated from 1.23 Mb of sequenced DNA. RESULTS: Genomic alterations with significant differences between PCL and DLBCL included MYD88, ETV6, PIM1, PRDM1, CXCR4, TP53, and CREBBP, while only MYD88 was significantly different between SCL and DLBCL. PCL cases were significantly enriched for the MCD molecular subtypes, which have an excellent response to BTKi. We report a patient with a durable complete response to BTKi consistent with their genomic profile. EBV status, CD274 amplification, and TMB status suggest that 38% of PCL patients may benefit from ICPI; however further study is warranted. CONCLUSION: CGP of PCLs reveals biomarkers, genomic alterations, and molecular classifications predictive of BTKi efficacy and potential ICPI efficacy. Given the limitations of standard of care for PCL, CGP is critical to identify potential therapeutic approaches for patients in this rare form of lymphoma. Oxford University Press 2023-01-18 /pmc/articles/PMC9847534/ /pubmed/36342081 http://dx.doi.org/10.1093/oncolo/oyac190 Text en © The Author(s) 2022. Published by Oxford University Press. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Hematologic Malignancies Severson, Eric A Haberberger, James Hemmerich, Amanda Huang, Richard S P Edgerly, Claire Schiavone, Kelsie Najafian, Adib Hiemenz, Matthew Lechpammer, Mirna Vergilio, Jo-Anne Lesser, Glenn Strowd, Roy Elvin, Julia Ross, Jeffrey S Hegde, Priti Alexander, Brian Singer, Samuel Ramkissoon, Shakti Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition |
title | Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition |
title_full | Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition |
title_fullStr | Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition |
title_full_unstemmed | Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition |
title_short | Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition |
title_sort | genomic profiling reveals differences in primary central nervous system lymphoma and large b-cell lymphoma, with subtyping suggesting sensitivity to btk inhibition |
topic | Hematologic Malignancies |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9847534/ https://www.ncbi.nlm.nih.gov/pubmed/36342081 http://dx.doi.org/10.1093/oncolo/oyac190 |
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