scholarly journals Targeted sequencing in DLBCL, molecular subtypes, and outcomes: a Haematological Malignancy Research Network report

Blood ◽  
2020 ◽  
Vol 135 (20) ◽  
pp. 1759-1771 ◽  
Author(s):  
Stuart E. Lacy ◽  
Sharon L. Barrans ◽  
Philip A. Beer ◽  
Daniel Painter ◽  
Alexandra G. Smith ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Molecular Subtypes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Classification Systems ◽  
Targeted Sequencing ◽  
Research Network ◽  
The Impact

Abstract Based on the profile of genetic alterations occurring in tumor samples from selected diffuse large B-cell lymphoma (DLBCL) patients, 2 recent whole-exome sequencing studies proposed partially overlapping classification systems. Using clustering techniques applied to targeted sequencing data derived from a large unselected population-based patient cohort with full clinical follow-up (n = 928), we investigated whether molecular subtypes can be robustly identified using methods potentially applicable in routine clinical practice. DNA extracted from DLBCL tumors diagnosed in patients residing in a catchment population of ∼4 million (14 centers) were sequenced with a targeted 293-gene hematological-malignancy panel. Bernoulli mixture-model clustering was applied and the resulting subtypes analyzed in relation to their clinical characteristics and outcomes. Five molecular subtypes were resolved, termed MYD88, BCL2, SOCS1/SGK1, TET2/SGK1, and NOTCH2, along with an unclassified group. The subtypes characterized by genetic alterations of BCL2, NOTCH2, and MYD88 recapitulated recent studies showing good, intermediate, and poor prognosis, respectively. The SOCS1/SGK1 subtype showed biological overlap with primary mediastinal B-cell lymphoma and conferred excellent prognosis. Although not identified as a distinct cluster, NOTCH1 mutation was associated with poor prognosis. The impact of TP53 mutation varied with genomic subtypes, conferring no effect in the NOTCH2 subtype and poor prognosis in the MYD88 subtype. Our findings confirm the existence of molecular subtypes of DLBCL, providing evidence that genomic tests have prognostic significance in non-selected DLBCL patients. The identification of both good and poor risk subtypes in patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) clearly show the clinical value of the approach, confirming the need for a consensus classification.

Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7538-7538 ◽  
Author(s):  
Joanne Soo ◽  
David Matthew Kurtz ◽  
Florian Scherer ◽  
Alexander F.M. Craig ◽  
Michael C. Jin ◽  
...  
Keyword(s):  
B Cell ◽  
Molecular Subtypes ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Circulating Tumor Dna ◽  
Targeted Sequencing ◽  
Cell Of Origin ◽  
Large B Cell Lymphoma ◽  
Tumor Dna ◽  
Large B Cell

7538 Background: Patients with diffuse large B cell lymphoma (DLBCL) exhibit significant differences in clinical outcome based on cell-of-origin (COO). Patients are categorized as having germinal-center-like (GCB) or activated-B-cell-like (ABC) disease based on RNA microarray and histopathological analyses of tumor biopsies. We recently described an accurate sequencing-based method for determination of COO in DLBCL utilizing stereotyped differences in mutations (Scherer et al., 2016). Here, we further explore the mutational patterns in patients with differing molecular subtypes of DLBCL based on sequencing of circulating tumor DNA. Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) to pretreatment plasma samples and matched germline from a cohort of 115 patients with DLBCL. We then identified somatic alterations, which were used to determine COO molecular subtypes as previously described. Finally, we compared mutational patterns in patients with GCB and non-GCB DLBCL. Results: We detected a significantly greater number of total mutations (GCB: 1766 ± 160 mutations per Mb of targeted sequencing; non-GCB: 1364 ± 150 mutations per Mb of targeted sequencing; p < 0.05) and coding mutations (GCB: 145 ± 21 mutations per Mb of targeted sequencing; non-GCB: 28 ± 8.5 mutations per Mb of targeted sequencing; p < 0.001), particularly in immunoglobulin (Ig) regions (p < 0.05). In addition, GCB and non-GCB samples exhibited distinct mutational patterns within Ig regions. GCB samples were enriched for mutations in regions of switch mu (Sμ) (p < 0.01) and IGHV2-70 (p < 0.01), while non-GCB samples were enriched for mutations in regions of IGHG3 (p < 0.03), IGHV4-34 (p < 0.03), and IGLL5 (p < 0.05). GCB samples were also significantly enriched for coding mutations in SOCS1 (p < 0.01), a gene not included in our original COO classifier. Conclusions: Patients with GCB and non-GCB DLBCL exhibit distinct mutational patterns across both Ig and non-Ig loci of the genome. These differences in mutational patterns can be used to classify molecular subtypes noninvasively, potentially providing further utility to noninvasive genotyping and liquid biopsies.

scholarly journals Elevated M-MDSCs in Circulation Are Indicative of Poor Prognosis in Diffuse Large B-Cell Lymphoma Patients

2021 ◽  
Vol 10 (8) ◽  
pp. 1768
Author(s):  
Zhitao Wang ◽  
Rui Jiang ◽  
Qian Li ◽  
Huiping Wang ◽  
Qianshan Tao ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
Suppressor Cells ◽  
B Cell Lymphoma ◽  
Pathological Process ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Accumulation Mechanism ◽  
Large B Cell

Myeloid-derived suppressor cells (MDSCs) are defined as negative regulators that suppress the immune response through a variety of mechanisms, which usually cluster in cancer, inflammation, and autoimmune diseases. This study aims to investigate the correlation between M-MDSCs and the clinical features of diffuse large B-cell lymphoma (DLBCL) patients, as well as the possible accumulation mechanism of M-MDSCs. The level of M-MDSCs is significantly increased in newly diagnosed and relapsed DLBCL patients. Regarding newly diagnosed DLBCL patients, the frequency of M-MDSCs is positively correlated with tumor progression and negatively correlated with overall survival (OS). More importantly, the level of M-MDSCs can be defined as a biomarker for a poor prognosis in DLBCL patients. Additionally, interleukin-35 (IL-35) mediates the accumulation of M-MDSCs in DLBCL patients. Anti-IL-35 treatment significantly reduces levels of M-MDSCs in Ly8 tumor-bearing mice. Thus, M-MDSCs are involved in the pathological process of DLBCL. Targeting M-MDSCs may be a promising therapeutic strategy for the treatment of DLBCL patients.

scholarly journals Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2945
Author(s):  
Mélanie Mercier ◽  
Corentin Orvain ◽  
Laurianne Drieu La Rochelle ◽  
Tony Marchand ◽  
Christopher Nunes Gomes ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
High Dose Methotrexate ◽  
Skeletal Involvement ◽  
Large B Cell Lymphoma ◽  
Dose Methotrexate ◽  
The Impact ◽  
Large B Cell

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1–0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04–0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.

scholarly journals Identification BCL6 and miR-30 family associating with Ibrutinib resistance in activated B-cell-like diffuse large B-cell lymphoma

2021 ◽  
Vol 38 (4) ◽  
Author(s):  
Jiazheng Li ◽  
Yan Huang ◽  
Yun Zhang ◽  
Jingjing Wen ◽  
Yanxin Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Venn Diagram ◽  
Potential Candidate ◽  
Large B Cell Lymphoma ◽  
Ibrutinib Resistance ◽  
Large B Cell ◽  
Geo Database

AbstractIbrutinib has clear efficacy for activated B-cell-like diffuse large B cell lymphoma (ABC-DLBCL) in previous clinical researches. However, the resistance of Ibrutinib has limited its therapeutic benefit and the potential mechanism remains unclear. This study was aimed to identify potential candidate genes and miRNA targets to overcome Ibrutinib resistance in ABC-DLBCL. First, two expression profiles were downloaded from the GEO database, which used to identify the DEGs related to Ibrutinib resistance in ABC-DLBCL cell lines by GEO2R analysis separately. And the common DEGs were obtained though Venn diagram. Then Gene ontology (GO) and pathway enrichment analysis were conducted by DAVID database. From STRING database, BCL6, IL10, IL2RB, IRF4, CD80, PRDM1and GZMB were determined to be the hub genes by protein–protein interaction (PPI) network. Through miRNA-mRNA targeting network, we found that BCL6, IRF4, CD80, and PRDM1 were common target genes of miR-30 family. The cBioPortal database showed that BCL6 had the highest level of genetic alterations among DLBCL. In addition, another expression profile from GEO database showed that BCL6 was significantly high expression in no responsive patients after Ibrutinib treatment, and the receiver operating characteristic (ROC) curve which was used to evaluate the relationship between BCL6 expression and its effect was 0.67. MTT assay showed that treatment with FX1 (a BCL6 inhibitor) can enhance the sensitivity of Ibrutinib in C481S BTK HBL-1 cells. The results suggested that BCL6 and miR-30 family maybe associate with Ibrutinib resistance in ABC-DLBCL.

scholarly journals The impact of structural factors on diagnostic delay in diffuse large B‐cell lymphoma

2019 ◽  
Vol 8 (4) ◽  
pp. 1416-1422
Author(s):  
Joanna C. Zurko ◽  
Raymond C. Wade ◽  
Amitkumar Mehta
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Diagnostic Delay ◽  
B Cell Lymphoma ◽  
Structural Factors ◽  
Large B Cell Lymphoma ◽  
The Impact ◽  
Large B Cell

scholarly journals New agents and regimens for diffuse large B cell lymphoma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Liang Wang ◽  
Lin-rong Li ◽  
Ken H. Young
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Classification Systems ◽  
Genetic Classification ◽  
Standard Regimen ◽  
Treatment Approaches ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractAs a widely recognized standard regimen, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is able to cure two-thirds patients with diffuse large B cell lymphoma (DLBCL), and the remaining patients suffer from refractory or relapsed disease due to resistance to R-CHOP and fare poorly. Unsatisfied outcomes for those relapsed/refractory patients prompted efforts to discover new treatment approaches for DLBCL, including chimeric antigen receptor T cells, bispecific T cell engagers, immunomodulatory drugs, immune checkpoint inhibitors, monoclonal antibodies, antibody–drug conjugates, molecular pathway inhibitors, and epigenetic-modifying drugs. Herein, up-to-date data about the most promising treatment approaches for DLBCL are recapitulated, and novel genetic classification systems are introduced to guide individualized treatment for DLBCL.

Anaplastic Variant of Diffuse Large B-cell Lymphoma Displays Intricate Genetic Alterations and Distinct Biological Features

2017 ◽  
Vol 41 (10) ◽  
pp. 1322-1332 ◽  
Author(s):  
Mingyang Li ◽  
Yixiong Liu ◽  
Yingmei Wang ◽  
Gang Chen ◽  
Qiongrong Chen ◽  
...  
Keyword(s):  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Biological Features ◽  
Large B Cell Lymphoma ◽  
Large B Cell
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