Genetics of diffuse large B-cell lymphoma

Abstract Diffuse large B-cell lymphoma (DLBCL), the most frequent subtype of lymphoid malignancy, remains a significant clinical challenge, as ∼30% of patients are not cured. Over the past decade, remarkable progress has been made in the understanding of the pathogenesis of this disease, spurred by the implementation of powerful genomic technologies that enabled the definition of its genetic and epigenetic landscape. These studies have uncovered a multitude of genomic alterations that contribute to the initiation and maintenance of the tumor clone by disrupting biological functions known to be critical for the normal biology of its cells of origin, germinal center B cells. The identified alterations involve epigenetic remodeling, block of differentiation, escape from immune surveillance, and the constitutive activation of several signal transduction pathways. This wealth of new information offers unique opportunities for the development of improved diagnostic and prognostic tools that could help guide the clinical management of DLBCL patients. Furthermore, a number of the mutated genes identified are potentially actionable targets that are currently being explored for the development of novel therapeutic strategies. This review summarizes current knowledge of the most common genetic alterations associated with DLBCL in relation to their functional impact on the malignant transformation process, and discusses their clinical implications for mechanism-based therapeutics.

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

Medical Oncology ◽

10.1007/s12032-021-01470-5 ◽

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.

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

The American Journal of Surgical Pathology ◽

10.1097/pas.0000000000000836 ◽

2017 ◽

Vol 41 (10) ◽

pp. 1322-1332 ◽

Cited By ~ 11

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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Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma

Blood ◽

10.1182/blood.2020006784 ◽

2021 ◽

Author(s):

Wendan Xu ◽

Philipp Berning ◽

Georg Lenz

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cell Receptor ◽

Genetic Alterations ◽

B Cell Receptor ◽

Special Focus ◽

Large B Cell Lymphoma ◽

Bcr Signaling ◽

Large B Cell

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category comprising distinct molecular subtypes characterized by diverse genetic aberrations that dictate patient outcome. As roughly one-third of DLBCL patients are not cured by current standard chemo-immunotherapy a better understanding of the molecular pathogenesis is warranted to improve outcome. B-cell receptor (BCR) signaling is crucial for the development, growth and survival of both normal and a substantial fraction of malignant B-cells. Various analyses revealed genetic alterations of central components of the BCR or its downstream signaling effectors in some subtypes of DLBCL. Thus, BCR signaling and the downstream NF-κB and PI3K cascades have been proposed as potential targets for the treatment of DLBCL patients. As one of the main effectors of BCR activation, PI3K mediated signals play a crucial role in the pathogenesis and survival of DLBCL. In this review, we summarize our current understanding of BCR signaling with a special focus on the PI3K pathway in DLBCL and how to utilize this knowledge therapeutically.

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The Spectrum of MYC Alterations in Diffuse Large B-Cell Lymphoma

Acta Haematologica ◽

10.1159/000505892 ◽

2020 ◽

Vol 143 (6) ◽

pp. 520-528

Author(s):

Yang Xia ◽

Xinlian Zhang

Keyword(s):

B Cell ◽

Clinical Outcomes ◽

Copy Number ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Gene Copy ◽

Novel Therapy ◽

Large B Cell Lymphoma ◽

Large B Cell

MYC, as a powerful transcription factor, plays a vital role in various cancers. The clinical significance of MYC alterations in diffuse large B-cell lymphoma (DLBCL) has been investigated for a long time. In this study, we comprehensively summarize the different alterations of MYC in DLBCL, including MYC overexpression, MYC translocations, MYC mutations, and increased gene copy number of MYC. Noteworthy, lone MYC overexpression or MYC translocation is not significantly associated with poor clinical outcomes, and their detrimental effects depend on the genetic alterations of BCL2 or BCL6. Both double-expressor DLBCL (DE-DLBCL), defined as overexpression of MYC and BCL2 proteins, and double-hit lymphoma (DHL), defined as a dual translocation of MYC together with BCL2 or BCL6, represent the distinct subgroups of DLBCL with inferior clinical outcomes. The mechanism may be that MYC activation induces cell proliferation, without the threat of the apoptotic brake in the presence of BCL2 overexpression. In addition, most of MYC mutations are present with favorable prognosis, and the nonsignificant effect of MYC copy number amplification has been observed. It has been proved that cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab show limited effects for DHL or DE-DLBCL, and the rituximab plus dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin seem to be efficacious for DHL. The novel therapy is urgently needed for clinical improvement in DHL and DE-DLBCL.

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MYC protein expression and genetic alterations have prognostic impact in patients with diffuse large B-cell lymphoma treated with immunochemotherapy

Haematologica ◽

10.3324/haematol.2013.086173 ◽

2013 ◽

Vol 98 (10) ◽

pp. 1554-1562 ◽

Cited By ~ 131

Author(s):

A. Valera ◽

A. Lopez-Guillermo ◽

T. Cardesa-Salzmann ◽

F. Climent ◽

E. Gonzalez-Barca ◽

...

Keyword(s):

Protein Expression ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Prognostic Impact ◽

Large B Cell Lymphoma ◽

Large B Cell

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TNFAIP3 (A20) Genetic Alterations In EBV Associated AIDS Related Lymphomas

Blood ◽

10.1182/blood.v116.21.802.802 ◽

2010 ◽

Vol 116 (21) ◽

pp. 802-802

Author(s):

Lisa B. Giulino ◽

Susan Mathew ◽

Wayne Tam ◽

Amy Chadburn ◽

Gianna Ballon ◽

...

Keyword(s):

In Situ Hybridization ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Ebv Infection ◽

Large B Cell Lymphoma ◽

Epstein Barr ◽

Large B Cell

Abstract Abstract 802 Introduction: AIDS related lymphomas (ARL) are a heterogeneous group of lymphoproliferative disorders that are frequently associated with Epstein Barr virus (EBV) infection. EBV expresses latent viral oncoproteins that constitutively activate the transcription factor NF-κB, a potent inducer of genes involved in B cell survival and proliferation (Keller SA et al, Blood 2006). Lymphomas that are not associated with EBV can also display increased NF-κB activity and recent reports have described mutations in regulators of NF-κB in subsets of B cell lymphomas. One of the frequently mutated regulatory genes is TNFAIP3, which encodes A20, an ubiquitin modifying enzyme involved in the termination of NF-κB signaling. Mutations resulting in the inactivation of A20 have been found in a significant proportion of marginal zone lymphoma (Novak U et al, Blood 2009), classical Hodgkin lymphoma, primary mediastinal B cell lymphoma (Schmitz R et al, J Exp Med 2009), and diffuse large B cell lymphoma (Compagno M et al, Nature 2009). In ARL the incidence of alterations in A20 and the relationship with EBV infection has not been described. Materials and Methods: We evaluated archival formalin fixed paraffin embedded tissue samples of ARL for genetic alterations in A20. Tissue was collected through an international collaboration between Weill Cornell Medical College in New York, USA and Siena University in Siena, Italy. A tissue microarray with 46 cases of ARL was prepared and characterization of lymphoma subtype and EBV viral status were determined by immunohistochemistry and in situ hybridization for Epstein-Barr encoded RNA. Fluorescent in situ hybridization (FISH) was used to evaluate for genomic deletions in A20, and translocations of cMYC, BCL-2 and BCL-6. Direct sequencing of the coding region and splice sites of A20 was performed to evaluate for additional genetic alterations. Immunohistochemistry was used to evaluate for the presence of A20 protein. Results: Fluorescent in situ hybridization revealed A20 monoallelic or biallelic deletion in 6 of 25 cases (24%). A20 point mutations were found in 3 of 23 cases (13%). Nonsense mutations coding for a premature stop codon in exon 2 were seen in 2 cases. The third case was found to have a missense mutation in exon 7 resulting in an amino acid change. Two of the 3 cases with an A20 point mutation had A20 deletion in the complementary allele indicating biallelic alteration of the A20 gene. Immunohistochemistry for A20 was performed and is reported for the first time in this abstract. Absence of A20 protein was demonstrated in 4 of 33 samples (12%). Included among the cases negative for A20 on immunohistochemistry is the single case with biallelic A20 deletion demonstrated by FISH. In total 10 of 39 (26%) cases with adequate sample for evaluation were determined to have inactivation of A20 by FISH, sequencing, immunohistochemistry, or a combination. A20 inactivation was seen among all histologic subtypes of ARL including Burkitt lymphoma (n=2), diffuse large B cell lymphoma of the germinal center B cell (n=2) and non-germinal center B cell (n=2), plasmablastic lymphoma (n=3) and B cell lymphoma, unclassifiable, intermediate between BL and diffuse large B cell lymphoma (n=1). Interestingly, the incidence of EBV infection was higher in cases with A20 inactivation than in those with intact A20. EBV was present in 6/10 cases with A20 alteration (60%) vs. 8/29 cases with intact A20 (28%). The EBV latent viral protein LMP-1, which activates NF-κB, was not expressed in cases with A20 alteration. Conclusions: This is the first report to demonstrate A20 inactivation in EBV-associated lymphoma. A20 molecular analysis has been previously reported in Hodgkin Lymphoma (HL) where A20 inactivation and EBV infection were found to be almost mutually exclusive (Schmitz R et al, J Exp Med 2009). The EBV gene expression pattern differs in HL and ARL. In HL EBV expresses the viral oncoprotein LMP-1, which leads to constitutive activation of NF-κB. In ARL viral gene expression is more heterogeneous and in this cohort of ARL, LMP-1 was not expressed in any of the cases with EBV infection and A20 loss. Our data indicate that A20 may represent a tumor suppressor gene in a significant subset of ARL and that A20 inactivation may be associated with positive EBV status. In EBV related lymphoma inactivation of A20 may be an alternative mechanism of NF-κB upregulation in the absence of LMP-1. Disclosures: No relevant conflicts of interest to declare.

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TP53 Aberrations By FISH in CLL and Complex Karyotype at Transformation Predict for Worse Outcome in Diffuse Large B-Cell Lymphoma - Richter Transformation: A Single Institution Series of 75 DLBCL-RT Cases

Blood ◽

10.1182/blood-2018-99-112242 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2984-2984 ◽

Cited By ~ 2

Author(s):

Shiraz Fidai ◽

Madina Sukhanova ◽

Brian C.-H. Chiu ◽

Y. Lynn Lynn Wang ◽

Wendy Stock ◽

...

Keyword(s):

B Cell ◽

Germinal Center ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Survival Outcome ◽

Complex Karyotype ◽

Large B Cell Lymphoma ◽

Trisomy 12 ◽

Large B Cell

Abstract Background: Richter transformation (RT), also known as Richter syndrome, is a rare complication of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) that has an aggressive clinical course and unfavorable prognosis. The majority of these transformations occur in the form of diffuse large B-cell lymphoma (DLBCL), and less frequently in the form of prolymphocytic leukemia (PLL), or classical Hodgkin lymphoma (cHL). We examined a series of RT cases with available CLL/SLL data diagnosed at our institution between 2000 and 2018 to identify clinical/biologic characteristics associated with adverse outcome. Design: After searching our pathology archives between the years 2000-2018, we identified a total of 83 RT cases: 75 DLBCL-RT (including 7 PLL-RT) and 8 cHL-RT. For the purposes of this study, we focused only on DLBCL-RT cases. All clinical, demographic, and pathologic data including cytogenetics (karyotype and FISH), immunohistochemistry (IHC), and flow cytometry were collected. Data points included age, gender, CLL/SLL histology (typical vs. atypical), CD5, CD38, ZAP-70 status, CLL karyotype, FISH [chromosomes 11q (ATM), trisomy 12, 13q, 14 (IGH), 17p(P53)]. In addition, time to transformation (months), site of transformation, transformation biopsy characteristics (germinal center vs. non-germinal center, CD5 status, along with MYC and BCL2 IHC status), and karyotype at transformation were collected. For the current analysis , karyotype and FISH data were dichotomized into (complex vs. non-complex) or (abnormality present vs. absent) respectively. Limited CLL treatment data was also collected but details on performance status, stage and IPI at transformation were not available. The clinical end point was overall survival (OS) determined as age at the time of transformation to death due to any cause, censoring patients without an event at last follow-up. Hazard ratios and 95% confidence intervals were derived from Cox proportional hazards regression models. Data analyses were performed using Stata®11. Results: Among DLBCL-RT patients, the median age at transformation was 66 years (range: 43-95). 87% of cases had antecedent CLL with a typical phenotype (CD5+, CD23+, FMC7-), 66% of CLL cases expressed CD38 (flow > 20% positivity) and 77% were positive for ZAP-70 (IHC). There was no correlation between CD38 expression and ZAP-70 (p=0.7). Fifty-three percent of the CLL cases harbored a complex karyotype. The most frequent abnormalities detected by FISH were TP53 aberrations (39%), followed by del13q (37%), Trisomy 12 (33%), IGH breaks (21%) and 11q/ATM deletion (17%). Transformation occurred at median of 59 months (0-352 range) after CLL diagnosis. DLBCL-RT was non-germinal center B-cell phenotype in 85% (n=27) of cases, with variable expression of CD5 (61%), p53 (50%), MYC (83%) and BCL2 (90%). EBER was infrequent at transformation (4%; n=23). Among DLBCL-RT, a total of 29 patients died at a median of 6 months (0-58 months) after RT diagnosis. In univariate analysis, age at transformation, type of CLL (typical vs. atypical), site (nodal vs. extranodal), CLL CD38 or ZAP-70 expression did not impact survival outcome. Only TP53 aberrations by FISH in antecendent CLL (p=0.02) (Figure 1) and the presence of complex karyotype at transformation were associated with adverse survival outcome (p=0.004) (Figure 2). MYC and/or BCL2 genetic alterations at transformation did not impact outcome. In a multivariable Cox model including both CLL TP53 aberrations and complex karyotype at transformation, only complex karyotype at transformation is weakly associated with outcome (p=0.09; hazard ratio 0.14 [0.015-1.36]; 95% CI) although this analysis is limited by the number of available patients with complete data (n=17). Conclusion: DLBCL-RT from an underlying CLL has a poor survival outcome and only TP53 alterations in the CLL and complex karyotype at transformation impacted survival. Figure. Figure. Disclosures Stock: Jazz Pharmaceuticals: Consultancy. Riedell:Bayer: Consultancy, Speakers Bureau; Novartis: Consultancy; Kite Pharmaceuticals: Consultancy, Speakers Bureau. Smith:BMS: Consultancy; Portola: Honoraria.

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Genomic Characterization of Diffuse Large B-Cell Lymphoma Transformation from Nodular Lymphocyte Predominant Hodgkin Lymphoma

Blood ◽

10.1182/blood-2019-125095 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1486-1486

Author(s):

Joo Y. Song ◽

Caoimhe Egan ◽

Alyssa Bouska ◽

Weiwei Zhang ◽

Qiang Gong ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

De Novo ◽

Cell Lymphoma ◽

Immune Surveillance ◽

B Cell Lymphoma ◽

Pi3k Pathway ◽

Large B Cell Lymphoma ◽

Frequent Mutations ◽

Large B Cell

Introduction: Transformed nodular lymphocyte predominant Hodgkin lymphoma (tNLPHL) with a typical diffuse large B-cell lymphoma (DLBCL) pattern is rare and not well studied by genomic analysis. We employed next generation sequencing and copy number analysis (CNA) to examine the pathogenesis of these tumors. Methods: We identified 19 cases of tNLPHL with DLBCL morphology and sheet-like growth from three institutions. NLPHL preceded transformation in 5 patients and was concurrent with transformation in 11. All cases of tNLPHL were sequenced using a targeted sequencing panel of 356 genes that included commonly mutated genes associated with lymphoma. We had 8 cases with matched germline DNA. We also performed CNA using Oncoscan on 18 cases of tNLPHL. Library preparation with paired end 100 bp sequencing and 6-10 million reads/case was performed on an Illumina HiSeq 2500. Fisher's exact test was used to compare the role of mutations in tNLPHL to three large series of de novo DLBCL. Results: The CNA showed frequent gains in REL and loss of CDKN2A. Mutation analysis showed frequent mutations of genes associated with the PI3K pathway such as SGK1 (26%), ZFP36L1 (16%), PIK3R1 (11%), and IL7R (11%), the NF-kB pathway such as CARD11 (21%), JUNB (21%), BCL10 (11%), NFKBIA (11%), TNFAIP3 (11%), histone/DNA modification such as KMT2D (26%), EP300 (21%), TET2 (11%), TET3 (11%), and the NOTCH pathway such as NOTCH2 (16%), NOTCH1 (1 case), CTBP2 (11%). Mutations in genes involved in immune surveillance and TP53 abnormalities were infrequent. Compared to de novo DLBCL, mutations in IL7R (10.5% vs 0.6%, p=0.03), JUNB (21% vs 4.2%, p=0.01), and SMARCAL1 (11% vs 0%, p=0.01) were significantly higher in tNLPHL than in germinal center B-cell (GCB) subtype of DLBCL. Conclusion: The mutational spectrum of tNLPHL resembles the DLBCL Cluster 4 of Chapuy et al (Nat Med, 2018), which were primarily GCB-DLBCL with frequent mutations in the PI3K pathway (SGK1), NF-kB pathway (CARD11, JUNB), and histone modification. The mutational spectrum is also distinctive in having frequent mutations that are not often seen together in DLBCL, such as TET2, JUNB and NOTCH2. Distinct from transformed follicular lymphoma, TP53 abnormalities and mutations affecting immune surveillance are uncommonly observed. This study provides new insights into the biology of tNLPHL and may highlight potential targets for therapy in the future. Disclosures Herrera: Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; AstraZeneca: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Kite Pharma: Consultancy, Research Funding.

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Integrative genomic analysis identifies key pathogenic mechanisms in primary mediastinal large B-cell lymphoma

Blood ◽

10.1182/blood.2019001126 ◽

2019 ◽

Vol 134 (10) ◽

pp. 802-813 ◽

Cited By ~ 20

Author(s):

Anja Mottok ◽

Stacy S. Hung ◽

Elizabeth A. Chavez ◽

Bruce Woolcock ◽

Adèle Telenius ◽

...

Keyword(s):

Gene Expression ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Genetic Alterations ◽

Janus Kinase ◽

Interferon Response ◽

Driver Genes ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Primary mediastinal large B-cell lymphoma (PMBL) represents a clinically and pathologically distinct subtype of large B-cell lymphomas. Furthermore, molecular studies, including global gene expression profiling, have provided evidence that PMBL is more closely related to classical Hodgkin lymphoma (cHL). Although targeted sequencing studies have revealed a number of mutations involved in PMBL pathogenesis, a comprehensive description of disease-associated genetic alterations and perturbed pathways is still lacking. Here, we performed whole-exome sequencing of 95 PMBL tumors to inform on oncogenic driver genes and recurrent copy number alterations. The integration of somatic gene mutations with gene expression signatures provides further insights into genotype–phenotype interrelation in PMBL. We identified highly recurrent oncogenic mutations in the Janus kinase-signal transducer and activator of transcription and nuclear factor κB pathways, and provide additional evidence of the importance of immune evasion in PMBL (CIITA, CD58, B2M, CD274, and PDCD1LG2). Our analyses highlight the interferon response factor (IRF) pathway as a putative novel hallmark with frequent alterations in multiple pathway members (IRF2BP2, IRF4, and IRF8). In addition, our integrative analysis illustrates the importance of JAK1, RELB, and EP300 mutations driving oncogenic signaling. The identified driver genes were significantly more frequently mutated in PMBL compared with diffuse large B-cell lymphoma, whereas only a limited number of genes were significantly different between PMBL and cHL, emphasizing the close relation between these entities. Our study, performed on a large cohort of PMBL, highlights the importance of distinctive genetic alterations for disease taxonomy with relevance for diagnostic evaluation and therapeutic decision-making.

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Molecular Genetics of Relapsed Diffuse Large B-Cell Lymphoma: Insight into Mechanisms of Therapy Resistance

Cancers ◽

10.3390/cancers12123553 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3553

Author(s):

Madeleine R. Berendsen ◽

Wendy B. C. Stevens ◽

Michiel van den Brand ◽

J. Han van Krieken ◽

Blanca Scheijen

Keyword(s):

B Cell ◽

Molecular Mechanisms ◽

Cell Lymphoma ◽

Treatment Options ◽

B Cell Lymphoma ◽

Therapy Resistance ◽

Genetic Alterations ◽

Comprehensive Overview ◽

Large B Cell Lymphoma ◽

Large B Cell

The majority of patients with diffuse large B-cell lymphoma (DLBCL) can be treated successfully with a combination of chemotherapy and the monoclonal anti-CD20 antibody rituximab. Nonetheless, approximately one-third of the patients with DLBCL still experience relapse or refractory (R/R) disease after first-line immunochemotherapy. Whole-exome sequencing on large cohorts of primary DLBCL has revealed the mutational landscape of DLBCL, which has provided a framework to define novel prognostic subtypes in DLBCL. Several studies have investigated the genetic alterations specifically associated with R/R DLBCL, thereby uncovering molecular pathways linked to therapy resistance. Here, we summarize the current state of knowledge regarding the genetic alterations that are enriched in R/R DLBCL, and the corresponding pathways affected by these gene mutations. Furthermore, we elaborate on their potential role in mediating therapy resistance, also in connection with findings in other B-cell malignancies, and discuss alternative treatment options. Hence, this review provides a comprehensive overview on the gene lesions and molecular mechanisms underlying R/R DLBCL, which are considered valuable parameters to guide treatment.

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