Genomic Profiling Reveals Differences in Primary Central Nervous System Lymphoma and Large B-Cell Lymphoma, With Subtyping Suggesting Sensitivity to BTK Inhibition.
DLCBL molecular subtyping
comprehensive genomic profiling
immune checkpoint inhibition
primary CNS lymphoma
Journal
The oncologist
ISSN: 1549-490X
Titre abrégé: Oncologist
Pays: England
ID NLM: 9607837
Informations de publication
Date de publication:
18 01 2023
18 01 2023
Historique:
received:
29
09
2021
accepted:
19
07
2022
pubmed:
8
11
2022
medline:
21
1
2023
entrez:
7
11
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 36342081
pii: 6808327
doi: 10.1093/oncolo/oyac190
pmc: PMC9847534
doi:
Substances chimiques
Myeloid Differentiation Factor 88
0
Biomarkers, Tumor
0
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e26-e35Informations de copyright
© The Author(s) 2022. Published by Oxford University Press.
Références
Eur J Cancer. 2017 Feb;72:12-19
pubmed: 28012348
Am J Hematol. 2018 Jul;93(7):953-962
pubmed: 29984868
Cancer Cell. 2021 Dec 13;39(12):1643-1653.e3
pubmed: 34739844
Blood. 2010 Oct 28;116(17):3268-77
pubmed: 20628145
Clin Cancer Res. 2012 Oct 1;18(19):5203-11
pubmed: 22837180
Proc Natl Acad Sci U S A. 2008 Sep 9;105(36):13520-5
pubmed: 18765795
Oncol Lett. 2016 May;11(5):3471-3476
pubmed: 27123138
Mod Pathol. 2009 Aug;22(8):1094-101
pubmed: 19448593
Hematol Oncol. 1990 May-Jun;8(3):141-5
pubmed: 2373491
Neuropathology. 2010 Jun;30(3):232-40
pubmed: 19925562
Leuk Lymphoma. 2016;57(6):1413-22
pubmed: 26699656
Blood. 2004 Jan 1;103(1):275-82
pubmed: 14504078
Acta Neuropathol. 2011 Dec;122(6):791-2
pubmed: 22020631
Leukemia. 2015 Mar;29(3):677-85
pubmed: 25189415
J Clin Oncol. 2013 Sep 1;31(25):3061-8
pubmed: 23569323
Neuropathol Appl Neurobiol. 2016 Apr;42(3):279-90
pubmed: 26111727
Basic Clin Neurosci. 2020 Jul-Aug;11(4):491-498
pubmed: 33613887
Curr Opin Neurol. 2019 Dec;32(6):886-894
pubmed: 31592789
Oncotarget. 2014 Jul 15;5(13):5065-75
pubmed: 24970810
J Natl Cancer Inst. 2018 Mar 1;110(3):316-320
pubmed: 29155997
Pathologica. 2010 Jun;102(3):83-7
pubmed: 21171509
Cancer Cell. 2020 Apr 13;37(4):551-568.e14
pubmed: 32289277
Cancer Discov. 2017 Sep;7(9):1018-1029
pubmed: 28619981
Blood. 2017 Jun 8;129(23):3071-3073
pubmed: 28356247
Nat Med. 2015 Aug;21(8):922-6
pubmed: 26193343
Br J Haematol. 2018 Nov;183(4):674-678
pubmed: 29076134
JCI Insight. 2017 Mar 23;2(6):e90196
pubmed: 28352655
Blood Cancer J. 2019 Aug 30;9(9):73
pubmed: 31471540
J Clin Oncol. 2013 Nov 1;31(31):3971-9
pubmed: 24101038
Int J Radiat Oncol Biol Phys. 2011 May 1;80(1):169-75
pubmed: 20584577
Appl Immunohistochem Mol Morphol. 2019 Feb;27(2):101-106
pubmed: 29084057
Br J Haematol. 2016 Aug;174(3):417-24
pubmed: 27018254
Eur J Cancer. 2019 Aug;117:121-130
pubmed: 31279304
Nature. 2010 Jan 7;463(7277):88-92
pubmed: 20054396
Cancer. 2002 Oct 1;95(7):1504-10
pubmed: 12237919
Neuropathology. 2018 Apr;38(2):125-134
pubmed: 29067721
Hematol Oncol. 2019 Dec;37(5):548-557
pubmed: 31418878
Blood. 2016 Jun 16;127(24):3004-14
pubmed: 26966091
Blood. 2018 Jan 11;131(2):182-190
pubmed: 29074501
Blood. 2016 Feb 18;127(7):869-81
pubmed: 26702065
Clin Cancer Res. 2015 Sep 1;21(17):3986-94
pubmed: 25991819
Neuro Oncol. 2010 Jul;12(7):736-44
pubmed: 20511181
Int J Radiat Oncol Biol Phys. 1995 Oct 15;33(3):663-73
pubmed: 7558957
N Engl J Med. 2017 Jun 22;376(25):2415-2426
pubmed: 28636851
N Engl J Med. 2015 Jan 22;372(4):311-9
pubmed: 25482239
Acta Neuropathol. 2012 Dec;124(6):905-6
pubmed: 23138649