Copy Number Alteration and Mutational Profile of High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements, Diffuse Large B-Cell Lymphoma with MYC-Rearrangement, and Diffuse Large B-Cell Lymphoma with MYC-Cluster Amplification

Miyaoka, Masashi; Kikuti, Yara Yukie; Carreras, Joaquim; Ito, Atsushi; Ikoma, Haruka; Tomita, Sakura; Kawada, Hiroshi; Roncador, Giovanna; Beà, Sı́lvia; Campo, Elı́as; Nakamura, Naoya

doi:10.3390/cancers14235849

Cited by 4 publications

(4 citation statements)

References 57 publications

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“…Histological analysis consisted of hematoxylin and eosin (H&E), Masson trichrome stain, immunohistochemical staining, and DNA in situ hybridization (FISH) with brake apart probes for BCL2 , BCL6 , and MYC (Vysis, Tokyo, Japan) [ 15 , 16 , 17 ]. Immunohistochemistry was performed following the manufacturer’s instructions (Leica Bond-Max autostainer, Leica Biosystems K.K., Tokyo, Japan) [ 18 ] and included a battery of primary antibodies as actin-SM, ALK-1, BCL2, BCL6, BTK D3H5, CD10, CD163, CD20 (L26), CD21, CD3, CD31, CD34, CD5, CD68, CD85A, CDK4, CK AE1/3, C-MYC, CSF1R, desmin, FOXP3, HLA-DP-DR, IL-10, MDM2, MIB-1, MUM1, p16, PD-1, PD-L1, PTEN, PTX3, RGS1, S100, and TNFRSF14 (HVEM).…”

Section: Methodsmentioning

confidence: 99%

“…The targeted NGS study was conducted using a custom gene panel that included 168 genes related to aggressive B-cell lymphomas and follicular lymphoma, based on the literature ( Appendix A , Table A1 ). The NGS tech-workflow used the protocol SureSelectXT, 4 pools of 8 libraries (equimolar), 4 runs, MiSeq 2 × 131, and kit 300 cycles v3 [ 17 ].…”

Section: Methodsmentioning

confidence: 99%

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Mutational Profile and Pathological Features of a Case of Interleukin-10 and RGS1-Positive Spindle Cell Variant Diffuse Large B-Cell Lymphoma

et al. 2023

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Diffuse large B-cell lymphoma with spindle cell morphology is a rare variant. We present the case of a 74-year-old male who initially presented with a right supraclavicular (lymph) node enlargement. Histological analysis showed a proliferation of spindle-shaped cells with narrow cytoplasms. An immunohistochemical panel was used to exclude other tumors, such as melanoma, carcinoma, and sarcoma. The lymphoma was characterized by a cell-of-origin subtype of germinal center B-cell-like (GCB) based on Hans’ classifier (CD10-negative, BCL6-positive, and MUM1-negative); EBER negativity, and the absence of BCL2, BCL6, and MYC rearrangements. Mutational profiling using a custom panel of 168 genes associated with aggressive B-cell lymphomas confirmed mutations in ACTB, ARID1B, DUSP2, DTX1, HLA-B, PTEN, and TNFRSF14. Based on the LymphGen 1.0 classification tool, this case had an ST2 subtype prediction. The immune microenvironment was characterized by moderate infiltration of M2-like tumor-associated macrophages (TMAs) with positivity of CD163, CSF1R, CD85A (LILRB3), and PD-L1; moderate PD-1 positive T cells, and low FOXP3 regulatory T lymphocytes (Tregs). Immunohistochemical expression of PTX3 and TNFRSF14 was absent. Interestingly, the lymphoma cells were positive for HLA-DP-DR, IL-10, and RGS1, which are markers associated with poor prognosis in DLBCL. The patient was treated with R-CHOP therapy, and achieved a metabolically complete response.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Mutational Profile and Pathological Features of a Case of Interleukin-10 and RGS1-Positive Spindle Cell Variant Diffuse Large B-Cell Lymphoma

et al. 2023

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“…The DLBCL-C group containing DDX3X mutations shares some similarities with the DGG-BL group since it includes EBV-positive tumors, with evidence of SHM and a high mutation burden (113). An additional study even estimates that 28% of DLBCL associated with altered MYC expression harbor DDX3X mutations that are particularly enriched in tumors defined as singlehit lymphoma (MYC but no other rearrangements) and c-MYC cluster-amplified lymphoma (140,141). Since it is known that alteration of MYC alone cannot induce a lymphoma and rely on other genetic alterations (61,142), DDX3X is a good candidate to investigate.…”

Section: Ddx3x Mutations Are Enriched In Myc-altered Gc-derived B-cel...mentioning

confidence: 99%

The RNA helicase DDX3 and its role in c-MYC driven germinal center-derived B-cell lymphoma

et al. 2023

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DDX3X is an RNA helicase with many functions in RNA metabolism such as mRNA translation, alternative pre-mRNA splicing and mRNA stability, but also plays a role as a regulator of transcription as well as in the Wnt/beta-catenin- and Nf-κB signaling pathways. The gene encoding DDX3X is located on the X-chromosome, but escapes X-inactivation. Hence females have two active copies and males only one. However, the Y chromosome contains the gene for the male DDX3 homologue, called DDX3Y, which has a very high sequence similarity and functional redundancy with DDX3X, but shows a more restricted protein expression pattern than DDX3X. High throughput sequencing of germinal center (GC)-derived B-cell malignancies such as Burkitt Lymphoma (BL) and Diffuse large B-cell lymphoma (DLBCL) samples showed a high frequency of loss-of-function (LOF) mutations in the DDX3X gene revealing several features that distinguish this gene from others. First, DDX3X mutations occur with high frequency particularly in those GC-derived B-cell lymphomas that also show translocations of the c-MYC proto-oncogene, which occurs in almost all BL and a subset of DLBCL. Second, DDX3X LOF mutations occur almost exclusively in males and is very rarely found in females. Third, mutations in the male homologue DDX3Y have never been found in any type of malignancy. Studies with human primary GC B cells from male donors showed that a loss of DDX3X function helps the initial process of B-cell lymphomagenesis by buffering the proteotoxic stress induced by c-MYC activation. However, full lymphomagenesis requires DDX3 activity since an upregulation of DDX3Y expression is invariably found in GC derived B-cell lymphoma with DDX3X LOF mutation. Other studies with male transgenic mice that lack Ddx3x, but constitutively express activated c-Myc transgenes in B cells and are therefore prone to develop B-cell malignancies, also showed upregulation of the DDX3Y protein expression during the process of lymphomagenesis. Since DDX3Y is not expressed in normal human cells, these data suggest that DDX3Y may represent a new cancer cell specific target to develop adjuvant therapies for male patients with BL and DLBCL and LOF mutations in the DDX3X gene.

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“…DLBCL with MYC-R and BCL2-R and/or BCL6-R is termed double- or triple-hit lymphoma (DHL and THL, respectively). All three types were reported to be associated with a poor prognosis [ 20 ]. However, to the best of our knowledge, these markers have not been used in prognostic scoring systems.…”

Section: Introductionmentioning

confidence: 99%

Artificial intelligence-based prognostic model accurately predicts the survival of patients with diffuse large B-cell lymphomas: analysis of a large cohort in China

Peng,

Su,

Guo

et al. 2024

BMC Cancer

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Background Diffuse large B-cell lymphomas (DLBCLs) display high molecular heterogeneity, but the International Prognostic Index (IPI) considers only clinical indicators and has not been updated to include molecular data. Therefore, we developed a widely applicable novel scoring system with molecular indicators screened by artificial intelligence (AI) that achieves accurate prognostic stratification and promotes individualized treatments. Methods We retrospectively enrolled a cohort of 401 patients with DLBCL from our hospital, covering the period from January 2015 to January 2019. We included 22 variables in our analysis and assigned them weights using the random survival forest method to establish a new predictive model combining bidirectional long-short term memory (Bi-LSTM) and logistic hazard techniques. We compared the predictive performance of our “molecular-contained prognostic model” (McPM) and the IPI. In addition, we developed a simplified version of the McPM (sMcPM) to enhance its practical applicability in clinical settings. We also demonstrated the improved risk stratification capabilities of the sMcPM. Results Our McPM showed superior predictive accuracy, as indicated by its high C-index and low integrated Brier score (IBS), for both overall survival (OS) and progression-free survival (PFS). The overall performance of the McPM was also better than that of the IPI based on receiver operating characteristic (ROC) curve fitting. We selected five key indicators, including extranodal involvement sites, lactate dehydrogenase (LDH), MYC gene status, absolute monocyte count (AMC), and platelet count (PLT) to establish the sMcPM, which is more suitable for clinical applications. The sMcPM showed similar OS results (P < 0.0001 for both) to the IPI and significantly better PFS stratification results (P < 0.0001 for sMcPM vs. P = 0.44 for IPI). Conclusions Our new McPM, including both clinical and molecular variables, showed superior overall stratification performance to the IPI, rendering it more suitable for the molecular era. Moreover, our sMcPM may become a widely used and effective stratification tool to guide individual precision treatments and drive new drug development.

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Copy Number Alteration and Mutational Profile of High-Grade B-Cell Lymphoma with MYC and BCL2 and/or BCL6 Rearrangements, Diffuse Large B-Cell Lymphoma with MYC-Rearrangement, and Diffuse Large B-Cell Lymphoma with MYC-Cluster Amplification

Cited by 4 publications

References 57 publications

Mutational Profile and Pathological Features of a Case of Interleukin-10 and RGS1-Positive Spindle Cell Variant Diffuse Large B-Cell Lymphoma

Mutational Profile and Pathological Features of a Case of Interleukin-10 and RGS1-Positive Spindle Cell Variant Diffuse Large B-Cell Lymphoma

The RNA helicase DDX3 and its role in c-MYC driven germinal center-derived B-cell lymphoma

Artificial intelligence-based prognostic model accurately predicts the survival of patients with diffuse large B-cell lymphomas: analysis of a large cohort in China

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