Genetic Landscape of Relapsed and Refractory Diffuse Large B-Cell Lymphoma: A Systemic Review and Association Analysis With Next-Generation Sequencing

In our research, we screened 1,495 documents, compiled the whole-exome sequencing data of several studies, formed a data set including 92 observations of RRDLBCL (Relapsed and refractory diffuse large B-cell lymphoma), and performed association analysis on the high-frequency mutations among them. The most common mutations in the data set include TTN, KMT2D, TP53, IGLL5, CREBBP, BCL2, MYD88, and SOCS1 etc. Among these, CREBBP, KMT2D, and BCL2 have a strong association with each other, and SOCS1 has a strong association with genes such as STAT6, ACTB, CIITA, ITPKB, and GNA13. TP53 lacks significant associations with most genes. Through SOM clustering, expression-level analysis and protein interaction analysis of common gene mutations, we believe that RRDLBCL can be divided into five main types. We tested the function of the model and described the clinical characteristics of each subtype through a targeted sequencing RRDLBCL cohort of 96 patients. The classification is stated as follows: 1) JAK-STAT-related type: including STAT6, SOCS1, CIITA, etc. The genetic lineage is similar to PMBL and cHL. Retrospective analysis suggests that this subtype responds poorly to induction therapy (R-CHOP, p < 0.05). 2) BCL-CREBBP type: Epigenetic mutations such as KMT2D and CREBBP are more common in this type, and are often accompanied by BCL2 and EZH2 mutations. 3) MCD type: including MYD88 and CD79B, PIM1 is more common in this subtype. 4) TP53 mutation: TP53 mutant patients, which suggests the worst prognosis (p < 0.05) and worst response to CART treatment. 5) Undefined type (Sparse item type): Major Genetic Change Lacking Type, which has a better prognosis and better response to CART treatment. We also reviewed the literature from recent years concerning the previously mentioned common gene mutations.

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Genetic Map of Relapsed and Refractory Diffuse Large B-cell Lymphoma: A Systemic Review and Association Analysis

10.21203/rs.3.rs-93266/v1 ◽

2020 ◽

Author(s):

Fan Gao ◽

Lei Tian ◽

Jing Wang ◽

Fei Dong ◽

Kai Hu ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

Strong Association ◽

Gene Mutations ◽

B Cell Lymphoma ◽

Data Set ◽

Common Gene ◽

Large B Cell Lymphoma ◽

The Common ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype of non-Hodgkin lymphoma (NHL). In recent years, a deeper understanding of the genetic subtypes of diffuse large B lymphoma has been reached, and these advances have also been applied to research on relapsed and refractory diffuse large B-cell lymphoma (RRDLBCL). We screened 1495 documents, compiled the whole-exome sequencing data of several studies, formed a data set including 92 observations, and performed association analysis on the high-frequency mutations among them. The most common mutations in the data set include TTN (34/92, 37.0%), KMT2D (29/92, 31.5%), TP53 (25/92, 27.2%), IGLL5 (25/92, 27.2%), CREBBP (21 /92, 22.8%), BCL2 (21/92, 22.8%), MYD88 (20/92, 21.7%), and SOCS1 (19/92, 20.7%). Among these, CREBBP, KMT2D, and BCL2 have a strong association with each other, and SOCS1 has a strong association with genes such as ACTB, CIITA, and GNA13. There is also a strong association between SOCS1 and STAT6. Though TP53 and MYD88 lack significant associations with most genes, the association between MYD88 and PIM1 is significant. Through SOM clustering and expression-level analysis of common gene mutations, we believe that RRDLBCL can be divided into four main types: (1) JAK-STAT-related type, including STAT6, SOCS1, ITPKB, CIITA, and B2M. The expression lineage is similar to PMBL and cHL. (2) EZB type: BCL2 and EZHZ are the main types of mutations. Epigenetic mutations such as KMT2D and CREBBP are more common in this type, and are often accompanied by BCL2 mutations. (3) MCD type, including MYD88, CD79B and PIM1. These genes are involved in the BCR signaling pathway and related pathways, and are connected by the common NF-κB pathway. (4) Undefined type (Sparse Mutation type). These patients are mainly individuals with sparse mutations, including some patients with TP53 mutations (30.3%, 10/33), but who generally lack characteristic mutations. Among the common gene mutations, the expression changes in BCL2, PIM1, STAT6, ITPKB, and GNA13 have more significant prognostic significance. We also reviewed the literature from recent years concerning the previously mentioned common gene mutations.

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PD-L1 gene alterations identify a subset of diffuse large B-cell lymphoma harboring a T-cell–inflamed phenotype

Blood ◽

10.1182/blood-2018-10-879015 ◽

2019 ◽

Vol 133 (21) ◽

pp. 2279-2290 ◽

Cited By ~ 28

Author(s):

James Godfrey ◽

Sravya Tumuluru ◽

Riyue Bao ◽

Michael Leukam ◽

Girish Venkataraman ◽

...

Keyword(s):

T Cell ◽

B Cell ◽

Immune Escape ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Data Set ◽

Large B Cell Lymphoma ◽

Programmed Death ◽

Large B Cell ◽

Gene Alterations

Abstract Programmed death-ligand 1 (PD-L1) expression on malignant cells is a dominant immune escape mechanism across a variety of human cancers. A unique genetic mechanism underlying PD-L1 upregulation has been uncovered in classical Hodgkin lymphoma (cHL), in which copy gains of the chromosomal region (9p24.1) containing the programmed death-1 (PD-1) ligands PD-L1 and PD-L2 are recurrently observed. While chromosome 9p24.1 copy-number alterations are ubiquitous in cHL, they also occur in diffuse large B-cell lymphoma (DLBCL), albeit with a lower incidence. Here, fluorescence in situ hybridization was used to identify DLBCLs harboring PD-L1 gene alterations, thereby enabling a characterization of the immunogenomic landscape of these lymphomas. Among 105 DLBCL cases analyzed, PD-L1 alterations were identified in 27%. PD-L1 alterations were highly enriched among non–germinal center DLBCLs and exhibited robust PD-L1 protein expression. These lymphomas were heavily infiltrated by clonally restricted T cells and frequently downregulated human leukocyte antigen expression. RNA sequencing of PD-L1–altered DLBCLs revealed upregulation of genes involved in negative T-cell regulation and NF-κB pathway activation, while whole-exome sequencing identified frequent mutations in genes involved in antigen presentation and T-cell costimulation. Many of these findings were validated in a large external data set. Interestingly, DLBCL patients with PD-L1 alterations had inferior progression-free survival following front-line chemoimmunotherapy; however, in the relapsed/refractory setting, PD-L1 alterations were associated with response to anti-PD-1 therapy. Collectively, our results indicate that PD-L1 alterations identify a unique biological subset of DLBCL in which an endogenous antilymphoma immune response has been activated, and that is associated with responsiveness to PD-1 blockade therapy.

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B-cell Function Gene Mutations in Diffuse Large B-cell Lymphoma: A Retrospective Cohort Study

EBioMedicine ◽

10.1016/j.ebiom.2017.01.027 ◽

2017 ◽

Vol 16 ◽

pp. 106-114 ◽

Cited By ~ 5

Author(s):

Peng-Peng Xu ◽

Hui-Juan Zhong ◽

Yao-Hui Huang ◽

Xiao-Dong Gao ◽

Xia Zhao ◽

...

Keyword(s):

Cohort Study ◽

B Cell ◽

Retrospective Cohort ◽

Cell Function ◽

Cell Lymphoma ◽

Gene Mutations ◽

B Cell Lymphoma ◽

B Cell Function ◽

Large B Cell Lymphoma ◽

Large B Cell

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The rs78378222 prevalence and the copy loss of the protective allele A in the tumor tissue of diffuse large B-cell lymphoma

PeerJ ◽

10.7717/peerj.10335 ◽

2020 ◽

Vol 8 ◽

pp. e10335

Author(s):

Elena N. Voropaeva ◽

Yuriy L. Orlov ◽

Tatiana I. Pospelova ◽

Anna A. Gurageva ◽

Mikhail I. Voevoda ◽

...

Keyword(s):

B Cell ◽

Tumor Tissue ◽

Cell Lymphoma ◽

Gene Mutations ◽

B Cell Lymphoma ◽

Genome Wide Association Studies ◽

Protective Allele ◽

Large B Cell Lymphoma ◽

Risk Of Cancer ◽

Large B Cell

Background Rare single nucleotide polymorphisms (SNPs) are likely to be a crucial genetic factor for human diseases, including cancer. rs78378222 is rare SNP in 3′-untranslated region (UTR) of TP53 gene leading to disturbance of 3′-end mRNA processing. The frequency of rs78378222 varies in several studied populations. The meta-analysis of 34 genome-wide association studies indicated that rs78378222 was significantly associated with an increased risk of cancer overall. Bioinformatic analysis indicates that somatic loss of the protective A allele of rs78378222 occurs in the tumor tissue of some malignant. The goal of the current study is to document the rs78378222 prevalence and evaluate the copy loss status of the protective allele A in the tumor tissue of patients with diffuse large B-cell lymphoma (DLBCL). Methods Total DNA was isolated from FFPE-samples and peripheral blood of patients with DLBCL and comparable in age and sex controls. rs78378222 genotyping was performed by the PCR-RFLP method using restriction endonuclease HindIII. Direct Sanger’s sequencing was used to confirm the presence of C allele of the rs78378222. The search for TP53 gene mutations was carried out by Sanger’s direct sequencing method, according to the IARC protocol. Results The result of genotyping of 136 DNA samples from DLBCL tumor tissue suggested that frequency of the rs78378222 was 11/136 (8.1%). Rare allele C frequency was 11/272 (4.2%). A total of 5/11 DLBCL rs78378222 heterozygous samples had the heterozygosity loss in the TP53 gene. Only one of these cases was combined with TP53 gene mutations which have proven oncogenic potential—p.Arg196Gln, other four cases have not mutations in the coding regions of gene. Conclusions At the stages of DLBCL initiation or progression a loss of the protective allele A of rs78378222 occurs. Further efforts are needed to study possible molecular mechanisms underlying somatic alterations in DLBCL in this region of the TP53 3′-UTR as well as functional studies to illustrate how the presents of rs78378222 may affect tumor progression of lymphoma.

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Diffuse Large B-Cell Lymphoma Cell of Origin Determination from Formalin-Fixed Paraffin-Embedded Tissues

Blood ◽

10.1182/blood.v126.23.5052.5052 ◽

2015 ◽

Vol 126 (23) ◽

pp. 5052-5052 ◽

Cited By ~ 1

Author(s):

Zijun Yidan Xu-Monette ◽

Debrah Thompson ◽

Bonnie LaFleur ◽

Patrick Roche ◽

Monica Reinholz ◽

...

Keyword(s):

B Cell ◽

Molecular Diagnostics ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Ffpe Tissue ◽

Cell Of Origin ◽

Data Set ◽

Large B Cell Lymphoma ◽

Equity Ownership ◽

Large B Cell

Abstract Diffuse large B-cell lymphoma (DLBCL) consists of two distinct subtypes, Germinal Center B-cell (GCB) and Activated B-Cell (ABC), each with distinct prognostic and biological profiles. With the advent of new targeted therapeutic approaches for DLBCL treatment, molecular sub-typing of the patient's tumor has been proposed as an important step in therapeutic selection and recommended by 2016 WHO classification guideline. Gene expression-profiling (GEP) based subtyping is considered the gold-standard method for DLBCL molecular sub-typing, but this method was established using fresh frozen / non-fixed tissues on microarray platforms. Since fresh tissue is not routinely collected during patient diagnosis, it severely limits the ability to utilize this assay in routine clinical practice. Multiple immunohistochemical (IHC) approaches have been developed to approximate the GEP methods, but these techniques generally suffer from lower than desired agreement rates with GEP classifications, and require staining of 4 to 8 sections of limited biopsy material. Interpretation of the slides can also be variable, leading to low inter-observer reproducibility. We have developed a 12 gene GEP-based DLBCL cell-of-origin (COO) assay using the HTG EdgeSeq System specifically designed to use a minimal amount of FFPE tissue. To build this system, we profiled a total of 107 samples previously subtyped using the HG-U133 Plus 2.0 Affymetrix microarrray and algorithm (Visco C et al Leukemia 2013); this algorithm was then validated in an additional 58 samples. The methodology we have developed produces 92% concordance with the microarray-based approach. Briefly, 107 DLBCL cases, of which 58 were previously sub-typed as ABC and 49 cases as GCB, were used as the training cohort. After classifier training and cross-validation, a separate cohort of 58 cases were used to verify the performance of the assay/classification system. Approximately 5 mm2 of 5 µm thick FFPE tissue was used to generate the data set for each of the cases. In addition to the DLBCL COO classification, the assay also contains additional genes including potential drug targets, T-cell, B-cell, and macrophage biomarkers, and housekeeping/normalization genes. These markers could be used to further understand the nature of the tumor and potentially help identify the characteristics of atypical tumors and immune infiltrates in the microenvironment. Disclosures Thompson: HTG Molecular Diagnostics, Inc: Equity Ownership. LaFleur:HTG Molecular Diagnostics, Inc: Equity Ownership. Roche:HTG Molecular Diagnostics, Inc: Equity Ownership. Reinholz:HTG Molecular Diagnostics, Inc: Equity Ownership. Wineman:HTG Molecular Diagnostics, Inc: Equity Ownership. Botros:HTG Molecular Inc: Equity Ownership.

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Forkhead Box Protein P1 Expression in Mucosa-Associated Lymphoid Tissue Lymphomas Predicts Poor Prognosis and Transformation to Diffuse Large B-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2006.05.6150 ◽

2006 ◽

Vol 24 (16) ◽

pp. 2490-2497 ◽

Cited By ~ 98

Author(s):

Xavier Sagaert ◽

Pascale de Paepe ◽

Louis Libbrecht ◽

Vera Vanhentenrijk ◽

Gregor Verhoef ◽

...

Keyword(s):

B Cell ◽

Lymphoid Tissue ◽

Poor Prognosis ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Data Set ◽

Forkhead Box ◽

Large B Cell Lymphoma ◽

Trisomy 3 ◽

Large B Cell

Purpose Gene expression profiling studies have reported upregulated mRNA expression of forkhead box protein P1 (FOXP1) in response to normal B-cell activation and high expression in a poor prognosis subtype of diffuse large B-cell lymphoma (DLBCL). Recently, it was also found that FOXP1 rearrangements and expression of its protein occur in mucosa-associated lymphoid tissue (MALT) lymphomas. In this study, we investigated FOXP1 expression in its relationship to morphology, genetic features, and prognosis in a series of 70 MALT lymphomas. Patients and Methods All samples were morphologically reviewed and stained for FOXP1. Presence of structural and/or numeric aberrations of the FOXP1, BCL10, and MALT1 genes was investigated. For all patients, a complete clinical data set was collected. Results We detected nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of nongerminal center phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18. Conclusion The data presented show that FOXP1 expression is an independent prognostic factor in MALT lymphomas. The data also support the hypothesis that a subgroup of nongerminal center DLBCLs (those marked by FOXP1 expression and trisomy 3 and 18) might represent a large-cell variant of MALT lymphomas.

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A Study of Outcomes of Diffuse Large B Cell Lymphoma in the Elderly

Blood ◽

10.1182/blood.v118.21.4950.4950 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4950-4950

Author(s):

Marc Hoffmann ◽

Tahamtan Ahmadi ◽

Erin Cobain ◽

Alison Loren ◽

Noelle V Frey ◽

...

Keyword(s):

Elderly Patients ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Standard Chemotherapy ◽

Chop Regimen ◽

Data Set ◽

Large B Cell Lymphoma ◽

Frail Patients ◽

Large B Cell

Abstract Abstract 4950 Introduction: Despite improvements in outcome using chemoimmunotherapy, treating elderly patients with diffuse large B cell lymphoma (DLBCL) remains challenging. Reliable risk stratification beyond age is lacking and consequently elderly patients are often treated with reduced-dose therapeutic regimen with palliative intent. We retrospectively analyzed outcomes of DLBCL patients aged 65 and older treated at the University of Pennsylvania. Patients and method: We identified 41 patients (pts) with diagnosis of DLBCL and age >65 years. Median age was 74 years (range: 65–86). Eight pts (20%) were age 80 or older. There were no differences in IPI, elevated LDH, or bcl-2 expression, whereas bcl-6 expression was more common in patients >80 years with 75% (6/8) vs. 27% (24/33) (p=0.01). Overall, 31 pts were treated with R-CHOP, 2 pts with R-HyperCVAD and one pt with R-CVP. Seven patients with a median age of 77 years were considered too frail for standard chemotherapy and were treated with a “split R-CHOP” regimen consisting of: rituximab 375 mg/m2 day 1, cyclophosphamide 375 mg/m2 day 1 and 15, adriamycin 25 mg/m2 day 1 and 15, vincristine 1 mg day 1 and 15 and Prednisone 50 mg day 1–5 and day 15–19. Results: Overall, the complete remission (CR) rate was 56% with seven treatment related deaths (17%). For patients between 65 to 80 years of age and deemed fit for standard chemotherapy (n=28), CR rate was 57% with four treatment related deaths (14%). Among patients over 80 and deemed fit for standard chemotherapy (n=6), the CR rate was 50% with 2 treatment related deaths (33%). Frail patients treated with the “split R-CHOP regimen” (n=7) had a CR rate of 57% with one (14%) treatment related death. For all patients, the median progression-free survival (PFS) was 1 year with a median overall survival (OS) of 2 years. The median PFS for pts between 65 and 80 years of age treated with standard chemotherapy was 16 months. Median PFS in pts >80 years of age treated with standard chemotherapy was 7 months, whereas median PFS in frail pts treated with “split R-CHOP regimen” was 11.7 months. Conclusions: Our data reveal interesting findings about elderly pts treated for DLBCL. PFS and OS in general are poor as has been reported by others. In our data set, pts>80 years considered fit for standard chemotherapy, had a shorter PFS then fit patients between 65 to 80 years. Intriguingly, PFS among frail elderly patients treated with a “split R-CHOP” regimen appears to be superior to that of elderly deemed more robust who were treated with standard dose RCHOP-21. Though limited by small numbers, our institutional data suggest that frail patients can tolerate a modified R-CHOP regimen although survival remains short. Disclosures: No relevant conflicts of interest to declare.

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CD56-positive diffuse large B-cell lymphoma/leukemia with BCL6/MYC double-hit and multiple gene mutations: an indicator of poor prognosis?

Journal of International Medical Research ◽

10.1177/0300060520918087 ◽

2020 ◽

Vol 48 (5) ◽

pp. 030006052091808

Author(s):

Yanquan Liu ◽

Jianzhen Shen ◽

M. Awal Issah ◽

Tingbo Liu ◽

Huarong Zhou ◽

...

Keyword(s):

B Cell ◽

Poor Prognosis ◽

Cell Lymphoma ◽

Intrathecal Injection ◽

Gene Mutations ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Double Hit ◽

Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is the most common adult non-Hodgkin lymphoma (NHL) and is highly invasive, with a poor prognosis. The main clinical treatment for DLBCL involves chemotherapy or a combination of chemotherapy and targeted drugs. CD56 expression is considered as an indicator of poor prognosis in patients with acute myeloid leukemia and anaplastic large cell lymphoma; however, its role in DLBCL remains unclear. We report on a patient with CD56-positive DLBCL/leukemia with BCL6/ MYC double-hit, and DDX3X, LRP1B, SIN3A, and GNA13 gene mutations (stage IVA, prognostic index aaIPI = 2 points). The patient was treated with cyclophosphamide and prednisone pre-chemotherapy plus R-Hyper-CVAD AB and DA-EPOCH regimens. Lumbar puncture combined with intrathecal injection was performed to prevent central nervous system infiltration during hospitalization, and complete remission was confirmed. We also reviewed the literature to clarify the relevance of the unique clinical features associated with this case.

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Germinal Center B Cell-Like (GCB) and Activated B Cell-Like (ABC) Type of Diffuse Large B Cell Lymphoma (DLBCL): Analysis of Molecular Predictors, Signatures, Cell Cycle State and Patient Survival

Cancer Informatics ◽

10.1177/117693510700300004 ◽

2007 ◽

Vol 3 ◽

pp. 117693510700300 ◽

Cited By ~ 30

Author(s):

S. Blenk ◽

J. Engelmann ◽

M. Weniger ◽

J. Schultz ◽

M. Dittrich ◽

...

Keyword(s):

Cell Cycle ◽

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Marker Genes ◽

Data Set ◽

Large B Cell Lymphoma ◽

Germinal Center B Cell ◽

Large B Cell

Aiming to find key genes and events, we analyze a large data set on diffuse large B-cell lymphoma (DLBCL) gene-expression (248 patients, 12196 spots). Applying the loess normalization method on these raw data yields improved survival predictions, in particular for the clinical important group of patients with medium survival time. Furthermore, we identify a simplified prognosis predictor, which stratifies different risk groups similarly well as complex signatures. We identify specific, activated B cell-like (ABC) and germinal center B cell-like (GCB) distinguishing genes. These include early (e.g. CDKN3) and late (e.g. CDKN2C) cell cycle genes. Independently from previous classification by marker genes we confirm a clear binary class distinction between the ABC and GCB subgroups. An earlier suggested third entity is not supported. A key regulatory network, distinguishing marked over-expression in ABC from that in GCB, is built by: ASB13, BCL2, BCL6, BCL7A, CCND2, COL3A1, CTGF, FN1, FOXP1, IGHM, IRF4, LMO2, LRMP, MAPK10, MME, MYBL1, NEIL1 and SH3BP5. It predicts and supports the aggressive behaviour of the ABC subgroup. These results help to understand target interactions, improve subgroup diagnosis, risk prognosis as well as therapy in the ABC and GCB DLBCL subgroups.

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