Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance
Abstract
:Simple Summary
Abstract
1. Introduction
2. Molecular Classifications of DLBCL
3. Immunochemotherapy Resistance in DLBCL
4. Clonal Evolution of Relapsed DLBCL
5. Genetic Alterations and Biological Pathways Selectively Enriched in R/R DLBCL
5.1. MYC, BCL2, and BCL6 Gene Alterations
5.1.1. BCL2
5.1.2. MYC
5.1.3. BCL6
5.2. TP53 Gene Alterations
5.3. Mutations Targeting JAK-STAT Signaling
5.4. Role of Immune Escape in Relapsed/Refractory DLBCL
5.5. Gene Mutations Affecting Epigenetic Regulators in Relapsed/Refractory DLBCL
6. Therapies Targeting Relapse-Associated Drivers
6.1. BCL2 Inhibitors
6.2. MYC Inhibitors
6.3. Targeting the p53 Pathway
6.4. Targeting the JAK/STAT Pathway
6.5. Therapeutic Strategies in the Context of Immune Escape
6.6. Epigenetic Targeting
7. Conclusions and Future Directions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Study | Cohort Description | Cohort Size | Method | Genes Presenting R/R Enriched Variants in Paired Diagnosis-Relapse Analyses 1 | Genes Presenting R/R Enriched Variants in Comparison with Independent Primary Cohorts 2 |
---|---|---|---|---|---|
Jiang et al. 2014 [46] | Paired D-R samples | N = 7 (4/7 tLY) | WES | BCL2, EP300, B2M, CD58 | |
Morin et al. 2016 [51] | Paired D-R/R samples | N = 12 (9/12 tLY) | Targeted panel | STAT6, EZH2, FOXO1, SOCS1, KMT2D, CD79B, NFKBIE | |
R/R samples (taken after at least one cycle of immuno-chemotherapy) | N = 25 | WES Targeted panel | R/R samples compared with independent primary cohort: KMT2C, MPEG1, NFKBIZ, CCND3, STAT6, TP53, MYC, FOXO1 | ||
Juskevicius et al. 2016 [45] | Paired D-R samples (relapse following complete remission) | N = 20 | Targeted panel | KMT2D, MEF2B, TET2, PRDM1, PTEN, EBF1 | |
Non-relapsing samples (taken at diagnosis ≥4 years relapse-free) | N = 20 | Targeted panel | Diagnosis samples of relapsed patients compared with non-relapsing samples: KMT2D, BCL2, PTEN, PRDM1, MCL1, CARD11 | ||
Melchardt et al. 2016 [44] | Paired D-R/R samples | N = 24 | Targeted panel | TP53, RB1, EZH2 | Diagnosis samples of R/R patients compared with independent primary cohort: NOTCH1, SMARCA4, PIM1, KMT2D R/R samples compared with independent primary cohort: TP53, BCL2, MYC, RB1, ATM, EZH2 |
Park et al. 2016 [55] | Diagnosis samples of responsive (CR maintained > 1 year interval) vs. refractory patients (<1 year interval) | N = 7 responsive N = 6 refractory | WES | TP53, MYD88, B2M, PRDM15, FNBP4, AHR, CEP128, BRE, SORCS3, WDFY3, CXXC4 | |
Mareschal et al. 2016 [54] | Diagnosis samples of R/R patients (≤1 year interval) | N = 14 | WES | ABC: MYD88, TBL1XR1, IRF4, CD58, PCDH17, HIST1H1B, HIST1H1C, HIST1H1D GCB: BCL2, DUSP2, NFKBIA, BTG2, MEF2B | |
Greenawalt et al. 2017 [52] | Paired D-R/R samples | N = 8 | WES | CREBBP, BCL2 | |
R/R samples (after 1–8 cycles of R-CHOP) | N = 47 | R/R samples compared with independent primary cohort: CREBBP, BCL2, TP53, B2M, MYC, BTK | |||
Nijland et al. 2018 [53] | Paired D-R/R samples (patients that received 6–8 cycles of R-CHOP) | N = 6 | WES | SOCS1, PIM1, MYC, BCL2, BIRC3, BTG2, IRF4, SGK1, B2M, CALR, HLA-DR, HLA-B | Diagnosis and relapsed samples of R/R cohort compared with independent primary cohort: SOCS1, PIM1, MYC, HLA-DR, HLA-B |
Rushton et al. 2020 [34] | Paired D-R/R samples (tissue biopsies/ctDNA) | N = 57 | Targeted panel | MS4A1, KMT2D, CD79B, TBL1XR1, ZFP36L1, CARD11, BTG2, MYC, SOCS1, PIM1, TNFAIP3, MYD88, HIST1H1E, NFKBIE, TNFRSF14, BCL2, IRF4, SGK1, GNA13, B2M, FBXO11, TP53, CD58, EP300 | |
R/R ctDNA | N = 135 | R/R samples compared with independent primary cohort: KMT2D, TP53, CREBBP, FOXO1, NFKBIE, MS4A1 | |||
Isaev et al. 2020 [48] | Paired D-CNS relapse samples | N = 5 | WES | PIM1, ETV6 | |
Diagnosis samples of systemic and CNS relapsed patients (<1 year interval) vs. non-relapsing patients (≥5 years relapse free) | N = 62 systemic relapse N = 72 CNS relapse N = 89 Non-relapsing | Targeted panel WES | Diagnosis samples of CNS relapse compared with non-relapsing samples: MYD88, CD79B, PIM1 Diagnosis samples of refractory disease or systemic relapse compared with non-relapsing samples: TP53, MYD88, BCL2, HIST1H1E, HIST1H1C, FOXO1, BTG1, CIITA, CD58, ZFP36L1 |
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Berendsen, M.R.; Stevens, W.B.C.; van den Brand, M.; van Krieken, J.H.; Scheijen, B. Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance. Cancers 2020, 12, 3553. https://doi.org/10.3390/cancers12123553
Berendsen MR, Stevens WBC, van den Brand M, van Krieken JH, Scheijen B. Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance. Cancers. 2020; 12(12):3553. https://doi.org/10.3390/cancers12123553
Chicago/Turabian StyleBerendsen, Madeleine R., Wendy B. C. Stevens, Michiel van den Brand, J. Han van Krieken, and Blanca Scheijen. 2020. "Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance" Cancers 12, no. 12: 3553. https://doi.org/10.3390/cancers12123553