• Humans
• Cyclin D1/genetics
• Gene Rearrangement
• Male
• Lymphoma, B-Cell/genetics
• Lymphoma, B-Cell/pathology
• Lymphoma, Large B-Cell, Diffuse/genetics
• Lymphoma, Large B-Cell, Diffuse/pathology
• Middle Aged
• In Situ Hybridization, Fluorescence
• Female
• Aged

• inert non-Hodgkin lymphoma
• lymphoma
• marginal zone lymphoma
• mechanism
• targeted therapy

• hematological malignancies
• measurable residual disease
• precision diagnostics
• precision medicine
• targeted therapy

• Humans
• Precision Medicine
• In Situ Hybridization, Fluorescence
• Hematologic Neoplasms/diagnosis
• Hematologic Neoplasms/drug therapy
• Hematologic Neoplasms/genetics
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Myeloid, Acute/therapy

• EZH2
• ctDNA
• ddPCR
• follicular lymphoma
• liquid biopsy
• tazemetostat

• Humans
• Lymphoma, Follicular/diagnosis
• Lymphoma, Follicular/genetics
• Lymphoma, Follicular/drug therapy
• Enhancer of Zeste Homolog 2 Protein/genetics
• Neoplasm Recurrence, Local
• Mutation
• Biopsy
• Liquid Biopsy
• Recurrence

• Epigenetics
• Genetics
• Molecular biology
• Omics
• Transcriptomics

• CtDNA
• IGH-BCL2 translocation
• cell-free DNA (cfDNA)
• droplet digital (ddPCR)
• liquid biopsy
• lymphoma
• measurable (minimal) residual disease (MRD)
• whole genome sequence (WGS)

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) are the most common forms of aggressive and indolent lymphoma, respectively. The majority of patients are cured by standard R-CHOP immunochemotherapy, but 30%–40% of DLBCL and 20% of FL patients relapse or are refractory (R/R). DLBCL and FL are phenotypically and genetically hereterogenous B-cell neoplasms. To date, the diagnosis of DLBCL and FL has been based on morphology, immunophenotyping and cytogenetics. However, next-generation sequencing (NGS) is widening our understanding of the genetic basis of the B-cell lymphomas. In this review we will discuss how integrating the NGS-based characterization of somatic gene mutations with diagnostic or prognostic value in DLBCL and FL could help refine B-cell lymphoma classification as part of a multidisciplinary pathology work-up. We will also discuss how molecular testing can identify candidates for clinical trials with targeted therapies and help predict therapeutic outcome to currently available treatments, including chimeric antigen receptor T-cell, as well as explore the application of circulating cell-free DNA, a non-invasive method for patient monitoring. We conclude that molecular analyses can drive improvements in patient outcomes due to an increased understanding of the different pathogenic pathways affected by each DLBCL subtype and indolent FL vs R/R FL.

• Next-generation sequencing
• Prognosis
• Molecular analysis
• Targeted therapy
• Chimeric antigen receptor T-cell therapy
• Personalized medicine

• DLBCL
• molecular classification
• molecular diagnostics
• signaling pathway
• targeted therapy

• Mutation
• blood cell counts
• diffuse large-B cell lymphoma
• early progression
• prognosis
• response to therapy

• CD70
• HBV infection
• diffuse large B-cell lymphoma
• genetic aberration
• immune evasion

• Animals
• Humans
• Mice
• B-Lymphocytes/pathology
• CD27 Ligand/genetics
• CD8-Positive T-Lymphocytes/pathology
• Epstein-Barr Virus Infections
• Lymphoma, Large B-Cell, Diffuse/genetics
• Lymphoma, Large B-Cell, Diffuse/pathology
• Tumor Microenvironment

• STINT
• Swedish Cancer Society
• Radiumhemmets Forskningsfonder

• Humans
• Lymphoma/diagnosis
• Lymphoma/genetics
• Lymphoma/therapy
• Genomics/methods
• Precision Medicine
• High-Throughput Nucleotide Sequencing
• Clinical Decision-Making
• Neoplasms

• 26819 Cancer Research UK
• P30 CA008748 NCI NIH HHS
• R01 CA154947 NCI NIH HHS

• cancer microenvironment
• apoptosis
• cancer therapeutic resistance
• cell signalling
• b-cell lymphoma

• Adult
• Antineoplastic Agents
• Bridged Bicyclo Compounds, Heterocyclic
• Cell Line, Tumor
• Drug Resistance, Neoplasm
• Humans
• Lymphoma, B-Cell
• Lymphoma, Mantle-Cell
• Myeloid Cell Leukemia Sequence 1 Protein
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Tumor Microenvironment
• bcl-X Protein

• KWF Kankerbestrijding (Dutch Cancer Society)

• (epi)genetics
• biomarkers
• comprehensive molecular profiling
• lymphoid malignancies
• precision medicine
• single-cell sequencing

• Genomics
• Humans
• Lymphoma/diagnosis
• Lymphoma/genetics
• Lymphoma/therapy
• Neoplasms/genetics
• Precision Medicine
• Prognosis

• Cancer Research UK
• Ministerio de Ciencia, Innovación y Universidades
• Cancer Research UK
• European Research Council
• Swedish Cancer Society
• Swedish Research Council
• Knut and Alice Wallenberg Foundation
• Karolinska Institutet
• Radiumhemmets Forskningsfonder

Inborn errors of immunity-associated lymphomas are characterized by distinct clinical features and genetic signatures.

Patients with inborn errors of immunity (IEI) have a higher risk of developing cancer, especially lymphoma. However, the molecular basis for IEI-related lymphoma is complex and remains elusive. Here, we perform an in-depth analysis of lymphoma genomes derived from 23 IEI patients. We identified and validated disease-causing or -associated germline mutations in 14 of 23 patients involving ATM, BACH2, BLM, CD70, G6PD, NBN, PIK3CD, PTEN, and TNFRSF13B. Furthermore, we profiled somatic mutations in the lymphoma genome and identified 8 genes that were mutated at a significantly higher level in IEI-associated diffuse large B-cell lymphomas (DLBCLs) than in non-IEI DLBCLs, such as BRCA2, NCOR1, KLF2, FAS, CCND3, and BRWD3. The latter, BRWD3, is furthermore preferentially mutated in tumors of a subgroup of activated phosphoinositide 3-kinase δ syndrome patients. We also identified 5 genomic mutational signatures, including 2 DNA repair deficiency-related signatures, in IEI-associated lymphomas and a strikingly high number of inter- and intrachromosomal structural variants in the tumor genome of a Bloom syndrome patient. In summary, our comprehensive genomic characterization of lymphomas derived from patients with rare genetic disorders expands our understanding of lymphomagenesis and provides new insights for targeted therapy.

• China/epidemiology
• Hepatitis B/complications
• Hepatitis B/diagnosis
• Hepatitis B/genetics
• Hepatitis B Surface Antigens/analysis
• Hepatitis B Surface Antigens/genetics
• Hepatitis B Surface Antigens/therapeutic use
• Hepatitis B virus/genetics
• Humans
• Lymphoma, Follicular/drug therapy
• Lymphoma, Follicular/genetics
• Lymphoma, Large B-Cell, Diffuse/drug therapy
• Tumor Microenvironment

• CTCL
• IL-22
• cutaneous T-cell lymphoma
• interleukin-22
• miR-26

• Animals
• Cell Line, Tumor
• DNA-Binding Proteins/genetics
• Down-Regulation
• Gene Expression Regulation, Neoplastic
• Humans
• Interleukins
• Lymphoma, T-Cell, Cutaneous/drug therapy
• Lymphoma, T-Cell, Cutaneous/genetics
• Mice
• MicroRNAs/metabolism
• RGS Proteins/genetics
• Skin Neoplasms/pathology
• Sorting Nexins/genetics
• Sorting Nexins/metabolism
• Transcription Factors/genetics
• Interleukin-22

• 17K09914 (HT) JSPS KAKENHI
• The Japanese Society of Hematology Research Grant (SI)

Zanubrutinib demonstrated deep and durable responses and a favorable safety profile in R/R MCL at median 35.3 months follow-up.

Bruton tyrosine kinase (BTK) inhibitor is an established treatment for relapsed/refractory (R/R) mantle cell lymphoma (MCL). Zanubrutinib, a highly selective BTK inhibitor, is approved for patients with MCL who have received ≥1 prior therapy. We report the long-term safety and efficacy results from the multicenter, open-label, phase 2 registration trial of zanubrutinib. Patients (n = 86) received oral zanubrutinib 160 mg twice daily. The primary endpoint was the overall response rate (ORR), assessed per Lugano 2014. After a median follow-up of 35.3 months, the ORR was 83.7%, with 77.9% achieving complete response (CR); the median duration of response was not reached. Median progression-free survival (PFS) was 33.0 months (95% confidence interval [CI], 19.4-NE). The 36-month PFS and overall survival (OS) rates were 47.6% (95% CI, 36.2-58.1) and 74.8% (95% CI, 63.7-83.0), respectively. The safety profile was largely unchanged with extended follow-up. Most common (≥20%) all-grade adverse events (AEs) were neutrophil count decreased (46.5%), upper respiratory tract infection (38.4%), rash (36.0%), white blood cell count decreased (33.7%), and platelet count decreased (32.6%); most were grade 1/2 events. Most common (≥10%) grade ≥3 AEs were neutrophil count decreased (18.6%) and pneumonia (12.8%). Rates of infection, neutropenia, and bleeding were highest in the first 6 months of therapy and decreased thereafter. No cases of atrial fibrillation/flutter, grade ≥3 cardiac AEs, second primary malignancies, or tumor lysis syndrome were reported. After extended follow-up, zanubrutinib demonstrated durable responses and a favorable safety profile in R/R MCL. The trial is registered at ClinicalTrials.gov as NCT03206970.

Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma and related to autoimmune diseases (AIDs). Primary B-cell receptor-mediated AIDs are associated with poor clinical outcome of DLBCL. To further determine the role of immunological alterations on disease progression, our study integrated genomic and transcriptomic analyses on DLBCL with multiple abnormal immunologic markers.

The clinical data of 1,792 patients with newly diagnosed DLBCL were collected, with DNA- and RNA-sequencing conducted for 164 and 127 patients, respectively. Frequent gene mutations and the involved dysregulated pathways, along with gene expression pattern and tumor microenvironment alternations, were analyzed and compared based on the immune status of the patients.

DLBCL with multiple abnormal immunologic markers demonstrated a variety of characteristics including elevated serum lactic dehydrogenase level, inferior prognosis, and dysregulated cell cycle and immune response, as well as activated oxidative phosphorylation pathway and increased Th1/Th2 and Th17/Treg ratios, which were highly similar as those that occur in AIDs.

We piloted the description of the clinical and genetic features of DLBCL with multiple abnormal immunologic markers, illustrated possible mechanisms of disease progression, and provided a clinical rationale of mechanism-based targeted therapy in this subset of DLBCL.

• National Natural Science Foundation of China
• Samuel Waxman Cancer Research Foundation

Multiple myeloma is an incurable malignancy of plasma cells resulting from impaired terminal B cell development. Almost all patients with multiple myeloma eventually have a relapse. Many studies have demonstrated the importance of the various genomic mutations that characterize multiple myeloma as a complex heterogeneous disease. In recent years, next-generation sequencing has been used to identify the genomic mutation landscape and clonal heterogeneity of multiple myeloma. This is the first study, a prospective observational study, to identify somatic mutations in plasma cell disorders in the Thai population using targeted next-generation sequencing. Twenty-seven patients with plasma cell disorders were enrolled comprising 17 cases of newly diagnosed multiple myeloma, 5 cases of relapsed/refractory multiple myeloma, and 5 cases of other plasma cell disorders. The pathogenic mutations were found in 17 of 27 patients. Seventy percent of those who had a mutation (12/17 patients) habored a single mutation, whereas the others had more than one mutation. Fifteen pathogenic mutation genes were identified: ATM, BRAF, CYLD, DIS3, DNMT3A, FBXW7, FLT3, GNA13, IRF4, KMT2A, NRAS, SAMHD1, TENT5C, TP53, and TRAF3. Most have previously been reported to be involved in the RAS/MAPK pathway, the nuclear factor kappa B pathway, the DNA-repair pathway, the CRBN pathway, tumor suppressor gene mutation, or an epigenetic mutation. However, the current study also identified mutations that had not been reported to be related to myeloma: GNA13 and FBXW7. Therefore, a deep understanding of molecular genomics would inevitably improve the clinical management of plasma cell disorder patients, and the increased knowledge would ultimately result in better outcomes for the patients.

• Thailand
• genetic
• molecular
• multiple myeloma
• next-generation sequencing

• B-cell lymphoma
• Hippo pathway
• TP53 signaling pathway
• gene fusion
• mutated pathway
• prognosis

• Lymphoma
• Precision diagnostics
• Precision medicine
• Prognostication
• Therapy prediction

• Diffuse large B-cell lymphoma
• early failure to therapy
• gene expression
• genetic alterations
• prognostic factors

Both somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID). Dysregulation of these processes has been linked to B cell lymphomagenesis. Here we performed an in-depth analysis of diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) genomes. We characterized seven genomic mutational signatures, including two B cell tumor-specific signatures, one of which is novel and associated with aberrant SHM. We further identified two major mutational signatures (K1 and K2) of clustered mutations (kataegis) resulting from the activities of AID or error-prone DNA polymerase η, respectively. K1 was associated with the immunoglobulin (Ig) switch region mutations/translocations and the ABC subtype of DLBCL, whereas K2 was related to the Ig variable region mutations and the GCB subtype of DLBCL and FL. Similar patterns were also observed in chronic lymphocytic leukemia subtypes. Thus, alterations associated with aberrant CSR and SHM activities can be linked to distinct developmental paths for different subtypes of B cell lymphomas.

• Biomarkers, Tumor
• Chromosome Aberrations
• Computational Biology/methods
• DNA Copy Number Variations
• Genetic Predisposition to Disease
• Genetic Variation
• Genomics/methods
• High-Throughput Nucleotide Sequencing/methods
• Humans
• INDEL Mutation
• Leukemia, Lymphoid/diagnosis
• Leukemia, Lymphoid/genetics
• Lymphoma/diagnosis
• Lymphoma/genetics
• Molecular Diagnostic Techniques
• Prognosis
• Translocation, Genetic

MicroRNAs (miRNAs) with functional relevance have not been previously identified in mantle cell lymphoma (MCL). Here, we aimed to evaluate the relationships between miR-34a and miR-155-5p and MCL clinicopathology and prognosis.

Seventy-five paraffin-embedded tissue samples from patients with MCL who completed at least four cycles of chemotherapy from January 2006 to October 2016, and 27 samples from control patients with reactive lymphoid hyperplasia (RLH), were collected. MiRNA expression levels were measured by qRT-PCR.

The miR-155-5p levels were significantly higher in patients with MCL than in the controls. The Eastern Cooperative Oncology Group (ECOG) ≥ 2 and Sex-Determining Region Y-Box transcription factor 11 (SOX11) < median value (M) groups presented lower miR-34a expression than the ECOG < 2 and SOX11 ≥ M groups, respectively. MiR-155-5p expression differed between low, intermediate, and high MCL International Prognostic Index risk groups. The AUCs of miR-34a and miR-155-5p were 0.5819 and 0.7784, respectively. The median survival times of the miR-34a ≤ 0.2150 and miR-155-5p > 2.11 groups were shorter than those of the miR-34a > 0.2150 and miR-155-5p ≤ 2.11 groups, respectively.

Low miR-34a and elevated miR-155-5p levels may be correlated with poor prognosis in MCL.

• Mantle cell lymphoma
• SOX11
• miR-155-5p
• miR-34a
• prognostic marker
• survival

Purpose: Diffuse large B cell lymphoma (DLBCL) is one of the most common B cell lymphomas, which displays heterogeneous pathologies. Programmed cell death 1/ programmed cell death ligand 1 (PD-1/PD-L1) plays an essential role in immunosuppression in multiple malignancies. Signal transducer and activator of transcription 3 (STAT3)-positive patients also have an independently inferior clinical outcome. However, there are no reports on the effect of plasma soluble PD-L1 (sPD-L1) combined with plasma STAT3 on the prognosis of DLBCL. In this study, we investigate the relationships between plasma sPD-L1 combined with STAT3 and clinical prognosis of DLBCL.

Methods: Levels of plasma sPD-L1 and STAT3 were quantified using ELISA in eighty-seven DLBCL patients. Multiplexed immunofluorescence staining was performed to visualize the expression of PD-L1 in twenty-nine matched FFPE specimens from all patients.

Results: The survival analysis revealed that the progression-free survival (PFS) and overall survival (OS) in high sPD-L1 level group were poorer than that in low sPD-L1 level group (PFS, P < 0.001; OS, P < 0.001). Similarly, the PFS and OS in high STAT3 level group were also poorer than that in low STAT3 level group. Multivariate cox regression analysis showed that both high sPD-L1 and high STAT3 levels were the independent prognostic factors negatively affecting survival. In addition, patients with DLBCL having high levels of both sPD-L1 and STAT3 had a worse outcome than those patients having any one high or low levels of both (P < 0.001).

Conclusions: We therefore revealed that high levels of plasma sPD-L1 and STAT3 are associated with inferior outcome for DLBCL patients, suggesting that combined measurement of their levels in plasma may be a promising prognostic strategy for DLBCL patients.

• DLBCL
• STAT3
• biomarker
• prognosis
• sPD-L1

The molecular features of mantle cell lymphoma (MCL), including its increased incidence, and complex therapies have not been investigated in detail, particularly in East Asian populations. In this study, we performed targeted panel sequencing (TPS) and whole-exome sequencing (WES) to investigate the genetic alterations in Korean MCL patients. We obtained a total of 53 samples from MCL patients from five Korean university hospitals between 2009 and 2016. We identified the recurrently mutated genes such as SYNE1, ATM, KMT2D, CARD11, ANK2, KMT2C, and TP53, which included some known drivers of MCL. The mutational profiles of our cohort indicated genetic heterogeneity. The significantly enriched pathways were mainly involved in gene expression, cell cycle, and programmed cell death. Multivariate analysis revealed that ANK2 mutations impacted the unfavourable overall survival (hazard ratio [HR] 3.126; P = 0.032). Furthermore, TP53 mutations were related to worse progression-free survival (HR 7.813; P = 0.043). Among the recurrently mutated genes with more than 15.0% frequency, discrepancies were found in only 5 genes from 4 patients, suggesting comparability of the TPS to WES in practical laboratory settings. We provide the unbiased genetic landscape that might contribute to MCL pathogenesis and recurrent genes conferring unfavourable outcomes.

• Epstein-Barr Virus Infections
• Female
• Gene Expression Profiling
• Herpesvirus 4, Human/genetics
• Hodgkin Disease/genetics
• Humans
• Lymphoma, Large B-Cell, Diffuse/genetics
• Male
• Middle Aged
• Tumor Microenvironment

• CIHR

• haematological cancer
• cancer therapy

• Antibodies, Monoclonal/therapeutic use
• Antineoplastic Agents/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Humans
• Immunotherapy
• Lymphoma/immunology
• Lymphoma/pathology
• Lymphoma/therapy
• Molecular Targeted Therapy
• Precision Medicine
• Tumor Microenvironment/drug effects
• Tumor Microenvironment/immunology

• 20152208 Shanghai Municipal Education Commission

• B-cell lymphoma
• BCL2
• Germinal Center
• MYC
• Tigecycline
• Venetoclax