Risk Of Diffuse Large B-cell Lymphoma Research Articles

Mendelian randomization analysis reveals causal effects of inflammatory bowel disease and autoimmune hyperthyroidism on diffuse large B-cell lymphoma risk

The clinical phenomenon whereby diffuse large B-cell lymphoma (DLBCL) occurs in patients with a history of autoimmune disease (AD) has been noted, but it remains controversial. This study aimed to evaluate the causal associations between nine ADs and DLBCL via a Mendelian randomization (MR) study. Single-nucleotide polymorphism (SNP) obtained from published genome-wide association studies (GWAS) was chosen as instrumental variable (IV). A total of nine ADs of European ancestry including asthma (56,167 cases and 352,255 controls), psoriasis (4,510 cases and 212,242 controls), autoimmune hyperthyroidism (962 cases and 172,976 controls), inflammatory bowel disease (31,665 cases and 33,977 controls), type 1 diabetes (6,683 cases and 12,173 controls), multiple sclerosis (14,498 cases and 24,091 controls), sarcoidosis (2,046 cases and 215,712 controls), ankylosing spondylitis (9,069 cases and 1,550 controls), and celiac disease (12,041 cases and 12,228 controls), were set as the exposure and DLBCL (209 cases and 218,583 controls) of European ancestry as the outcome. Inverse-variance weighted (IVW) was used as the primary analysis method, and the weighted median and MR-Egger method were used as supplementary methods. The sensitivity analyses employed in this study include the MR-Egger intercept, MR-PRESSO global test, Cochran’s Q test, leave-one-out analysis, and funnel plot. IVW showed that inflammatory bowel disease (OR = 1.241, 95% CI 1.009–1.526, P = 0.040) and autoimmune hyperthyroidism (OR = 1.464, 95% CI 1.103–1.942, P = 0.008) increased the risk of DLBCL without significant heterogeneity or horizontal pleiotropy, and the results remained stable according to the leave-one-out analysis. The IVW results revealed no associations between the other seven ADs and DLBCL: asthma (OR = 0.782, 95% CI 0.395–1.546, P = 0.159), psoriasis (OR = 0.842, 95% CI 0.669–1.060, P = 0.143), type 1 diabetes (OR = 1.071, 95% CI 0.860–1.334, P = 0.537), multiple sclerosis (OR = 1.331, 95% CI 0.941–1.883, P = 0.105), sarcoidosis (OR = 1.324, 95% CI 0.861–2.038, P = 0.200), ankylosing spondylitis (OR = 1.884, 95% CI 0.776–4.573, P = 0.161), and celiac disease (OR = 1.003, 95% CI 0.854–1.178, P = 0.969). Although no significant heterogeneity or horizontal pleiotropy was detected in these seven ADs and DLBCL, these results did not pass the leave-one-out analysis; therefore, the results need to be interpreted with caution. Inflammatory bowel disease and autoimmune hyperthyroidism may increase the onset of DLBCL. The risk of DLBCL should be considered in specific types of ADs.

Causal association of physical activity with lymphoma risk: a Mendelian randomization analysis.

Controversial relationship of physical activity with lower lymphoma risk has been reported in observational studies. The purpose of this study was to explore the causal correlation of physical activity with lymphoma risk using two-sample Mendelian randomization (MR). Genetic variants associated with physical activity (moderate-to-vigorous physical activity (MVPA), average acceleration physical activity, number of days/week of moderate physical activity 10+ min, and number of days/week of vigorous physical activity 10+ min) and lymphoma [overall lymphoma, Hodgkin lymphoma, mature T/NK-cell lymphomas, diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma] were obtained from published genome-wide association studies (GWAS) and the FinnGen database and used as instrumental variables. Primary results were based on inverse variance-weighted (IVW) analysis and were described as odds ratio (OR) and 95% confidence interval (CI). Higher levels of genetically predicted MVPA (OR = 0.079, 95% CI: 0.021-0.300, P = 0.0002) and number of days/week of vigorous physical activity 10+ min (OR = 0.237, 95% CI: 0.098-0.573, P = 0.0014) were negatively associated with Hodgkin lymphoma risk. There was a weak negative association between high levels of genetically predicted MVPA (OR = 0.114, 95% CI: 0.015-0.856, P = 0.0348) and average acceleration physical activity (OR = 0.830, 95% CI: 0.705-0.976, P = 0.0243) and risk of DLBCL. No causal relationship was observed between physical activity and the risk of overall lymphoma, mature T/NK-cell lymphomas, and follicular lymphoma (P > 0.05). This study supported the causal relationship between higher physical activity levels and lower risks of Hodgkin lymphoma and DLBCL.

An assessment model for the efficacy of autologous CD19 chimeric antigen receptor T-cell therapy and relapse or refractory diffuse large B-cell lymphoma risk.

An assessment model for the efficacy of autologous CD19 chimeric antigen receptor T-cell therapy and relapse or refractory diffuse large B-cell lymphoma risk.

The association between statin use and non-Hodgkin lymphoma; a systematic review and meta-analysis

Introduction: Statins reduce the cancer risk; however, non-Hodgkin lymphoma (NHL) evidence remains controversial. Therefore, we aimed to evaluate the relationship between statin consumption and NHL risk using a systematic review and meta-analysis. Materials and Methods: In this systematic review and meta-analysis, international databases, including Scopus, PubMed, Web of Science, Cochrane, and Google Scholar search engines, were searched without a time limit up to September 21, 2023. Data analysis was performed using STATA 14 software, and the significance level was considered P<0.05. Results: The results of combining 13 studies (9 case-control studies and 4 cohort studies) with a total sample size of 1142 740 subjects showed that statin consumption could reduce NHL risk by 22% (RR: 0.78; 95% CI: 0.69, 0.88). Statin consumption in cohort studies reduced NHL risk by 14% (RR: 0.86; 95% CI: 0.77, 0.95), but in case-control studies, it reduced NHL risk by 26% (RR: 0.74; 95% CI: 0.62, 0.90). Furthermore, statin consumption reduced diffuse large B-cell lymphoma risk by 24% (RR: 0.76; 95% CI: 0.67, 0.87) and marginal zone risk by 26% (RR: 0.74; 95% CI: 0.59, 0.93). However, it did not affect reducing the risk of chronic lymphocytic leukemia/small lymphocytic lymphoma (RR: 0.94; 95% CI: 0.85, 1.05), follicular (RR: 0.96; 95% CI: 0.83, 1.10), plasma cell neoplasms (RR: 0.97; 95% CI: 0.70, 1.33), T cell lymphoma (RR: 0.81; 95% CI: 0.55, 1.19) and B cell lymphoma (RR: 0.94; 95% CI: 0.44, 2.01). Conclusion: Statin consumption significantly reduced the risk of NHL, diffuse large B-cell lymphoma, and marginal zone but did not affect other NHL types. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023469126) and Research Registry (UIN: reviewregistry1732) website.

HLA variations in patients with diffuse large B-cell lymphoma and association with disease risk and prognosis: a case-control study.

Human leukocyte antigen (HLA) polymorphisms have been associated with the development of various autoimmune diseases, as well as malignant neoplasms. Non-Hodgkin lymphomas (NHLs) are a heterogenous group of lymphoid malignancies in which a genetic substrate has been established and is deemed to play a crucial role in disease pathogenesis. This study aimed to identify whether variations in the HLA gene region were associated with diffuse large B-cell lymphoma (DLBCL) risk and prognosis. We defined HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1) alleles in 60 patients with DLBCL and compared the results to those found by 236 healthy adult donors from the bone marrow bank of Northern Greece. HLA typing was performed by two molecular methods, Sequence - Specific Oligonucleotide HLA typing (SSO) and Sequence - Specific Primer HLA typing (SSP), from white blood cells recovered from peripheral blood. The phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 between patients and controls were compared with the 2-sided Fisher's exact test. Results with p-value <0.05 were considered statistically significant. Odds Ratios with 95% Confidence Intervals were calculated to further strengthen the results. The 2-sided Fisher's exact test was also applied to alleles found only in one of the two groups, while the odds ratios together with the confidence intervals were corrected with Haldane-Anscombe method. Among the studied HLA polymorphisms, the frequency HLA-C*12 allele was significantly lower in patients with DLBCL compared with control subjects (6.7% vs. 34.7%, OR = 0.16, 95% CI: 0.04-0.44). Frequency of HLA-B*39 was significantly lower in patients with DLBCL compared with controls, but due to the low frequency of this polymorphism in the studied population and small sample size, determinations regarding the significance of this findings were limited. Survival analysis revealed that the presence of HLA-C*12 was not associated with improved or worsened overall and progression-free survival. No statistically significant associations were observed in the phenotypic frequencies of HLA-A, HLA-DQB1, HLA-DRB1 and the rest of HLA-B alleles between the control and DLBCL groups. Collectively, our results provide valuable insight regarding the role of HLA variations on DLBCL risk. Further studies are required to consolidate our findings and ascertain the clinical implications of these genetic variations on DLBCL management and prognosis.

Dissecting causal links between gut microbiota, inflammatory cytokines, and DLBCL: a Mendelian randomization study

AbstractCausal relationships between gut microbiota, inflammatory cytokines, and diffuse large B-cell lymphoma (DLBCL) remain elusive. In addressing this gap, our Mendelian randomization (MR) study used data from the MiBioGen consortium encompassing 211 microbiota taxa (n = 18 340), genome-wide association study meta-analyses of 47 inflammatory cytokines, and DLBCL cases and controls from the FinnGen consortium (cases, n = 1010; controls, n = 287 137). Through bidirectional MR analyses, we examined the causal links between gut microbiota and DLBCL and used mediation analyses, including 2-step MR and multivariable MR (MVMR), to identify potential mediating inflammatory cytokines. Our findings revealed that 4 microbiota taxa were causally associated with DLBCL, and conversely, DLBCL influenced the abundance of 20 taxa. Specifically, in the 2-step MR analysis, both the genus Ruminococcaceae UCG-002 (odds ratio [OR], 1.427; 95% confidence interval [CI], 1.011-2.015; P = .043) and the inflammatory cytokine monokine induced by gamma (MIG) (OR, 1.244; 95% CI, 1.034-1.487; P = .020) were found to be causally associated with an increased risk of DLBCL. Additionally, a positive association was observed between genus Ruminococcaceae UCG-002 and MIG (OR, 1.275; 95% CI, 1.069-1.520; P = .007). Furthermore, MVMR analysis indicated that the association between genus Ruminococcaceae UCG-002 and DLBCL was mediated by MIG, contributing to 14.9% of the effect (P = .005). In conclusion, our MR study provides evidence that supports the causal relationship between genus Ruminococcaceae UCG-002 and DLBCL, with a potential mediating role played by the inflammatory cytokine MIG.

Causal relationships of gut microbiota, plasma metabolites, and metabolite ratios with diffuse large B-cell lymphoma: a Mendelian randomization study.

Recent studies have revealed changes in microbiota constitution and metabolites associated with tumor progression, however, no causal relation between microbiota or metabolites and diffuse large B-cell lymphoma (DLBCL) has yet been reported. We download a microbiota dataset from the MiBioGen study, a metabolites dataset from the Canadian Longitudinal Study on Aging (CLSA) study, and a DLBCL dataset from Integrative Epidemiology Unit Open genome-wide association study (GWAS) project. Mendelian randomization (MR) analysis was conducted using the R packages, TwoSampleMR and MR-PRESSO. Five MR methods were used: MR-Egger, inverse variance weighting (IVW), weighted median, simple mode, and weighted mode. Reverse MR analyses were also conducted to explore the causal effects of DLBCL on the microbiome, metabolites, and metabolite ratios. Pleiotropy was evaluated by MR Egger regression and MR-PRESSO global analyses, heterogeneity was assessed by Cochran's Q-test, and stability analyzed using the leave-one-out method. 119 microorganisms, 1,091 plasma metabolite, and 309 metabolite ratios were analyzed. According to IVW analysis, five microorganisms were associated with risk of DLBCL. The genera Terrisporobacter (OR: 3.431, p = 0.049) andgenera Oscillibacter (OR: 2.406, p = 0.029) were associated with higher risk of DLBCL. Further, 27 plasma metabolites were identified as having a significant causal relationships with DLBCL, among which citrate levels had the most significant protective causal effect against DLBCL (p = 0.006), while glycosyl-N-tricosanoyl-sphingadienine levels was related to higher risk of DLBCL (p = 0.003). In addition, we identified 19 metabolite ratios with significant causal relationships to DLBCL, of which taurine/glutamate ratio had the most significant protective causal effect (p = 0.005), while the phosphoethanolamine/choline ratio was related to higher risk of DLBCL (p = 0.009). Reverse MR analysis did not reveal any significant causal influence of DLBCL on the above microbiota, metabolites, and metabolite ratios (p > 0.05). Sensitivity analyses revealed no significant heterogeneity or pleiotropy (p > 0.05). We present the first elucidation of the causal influence of microbiota and metabolites on DLBCL using MR methods, providing novel insights for potential targeting of specific microbiota or metabolites to prevent, assist in diagnosis, and treat DLBCL.

The Addition of Lenalidomide to R-CHOP Is Effective for Prevention of CNS Relapse in High-Risk Patients with Diffuse Large B-Cell Lymphoma

Central nervous system (CNS) relapse is an uncommon but devastating event in patients in diffuse large B-cell lymphoma (DLBCL). Although several prophylaxis attempts including intrathecal methotrexate and intravenous high-dose methotrexate were conducted to reduce the CNS relapse rate, the optimal management remained uncertain. Herein, we performed an open-label, multicenter trial to explore the efficacy and safety of the combination of lenalidomide and R-CHOP (R2-CHOP) for preventing the CNS relapse in the high-risk diffuse large B cell lymphoma. Eligible patients were aged 18-80 years, newly diagnosed DLBCL and high risk for CNS recurrence: CNS-IPI:4-6 or involvement of testicular, kidneys or adrenal glands. Lenalidomide orally 25 mg per day was administered on days 1 through 10 of each cycle and delivered concomitantly with standard dose R-CHOP-21 regimen. All patients received aspirin 100mg per day prophylaxis throughout. The primary endpoint was 2-year central nervous system relapse rates. The secondary endpoint were 2-year overall survival, progression-free survival, and treatment-emergent adverse events. This trial is registered with ClinicalTrials.gov, number NCT04544059. A total of 56 DLBCL patients with high-risk for CNS relapse were included in this study. The median age of the patients in this study was 57 years old (range 26-77） and 47.8% patients were female. 88.9% patients had a CNS-IPI score ≥4 and the left patients may be involved with testicular, kidneys or adrenal glands. With a median follow up of 20 months,45patients finished planned cycles of R2-CHOP treatment and only 2（4.4%） patient developed CNS relapse. The 2-year progression-free survival and overall survival were 77.8% and 79.7%, respectively. In summary, lenalidomide with R-CHOP is effective for prevention of CNS relapse in high-risk patients with diffuse large B-cell lymphoma. Keywords: Diffuse large B-cell lymphoma, central nervous system relapse, lenalidomide.

Antinuclear Antibodies Are Associated with an Increased Risk of Diffuse Large B-Cell Lymphoma.

Immune dysregulation is thought to increase the risk of non-Hodgkin lymphoma (NHL), but the evidence varies by subtype. We evaluated whether antinuclear antibodies (ANA), double-stranded DNA antibodies (anti-dsDNA), and extractable nuclear antigen antibodies (anti-ENA) were associated with the risk of common NHL subtypes in a nested case-control study. The autoantibodies were tested in serum collected years prior to NHL diagnosis in 832 cases and 809 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Logistic regression was used to determine odds ratios (ORs) and 95% confidence intervals (95% CI) for the association with NHL risk. No association was observed between ANA positivity and NHL risk overall (OR: 1.18, 95% CI: 0.88-1.58); however, ANA positivity was associated with an increased risk of diffuse large B-cell lymphoma (DLBCL) (OR: 1.83, 95% CI: 1.15-2.91), with 19.7% of cases and 12.2% of controls testing positive. The presence of either anti-ENA or anti-dsDNA was associated with an increased risk of NHL (OR: 2.93, 95% CI: 1.18-7.28), particularly DLBCL (OR: 3.51, 95% CI: 1.02-12.0) and marginal zone lymphoma (OR: 8.86, 95% CI: 1.26-62.0). Our study demonstrates that autoantibodies are associated with an elevated risk of DLBCL, providing support for autoimmunity as a risk factor.

Prognostic value of whole-body dynamic 18F-FDG PET/CT Patlak in diffuse large B-cell lymphoma

ObjectiveThis study aims to investigate the significance of interim whole-body dynamic 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) Patlak parameters for predicting the prognosis of patients with diffuse large B-cell lymphoma. To estimate the predictive value of the whole-body dynamic 18F-FDG PET/CT Patlak parameter for 2-year progression-free survival (PFS) and 2-year overall survival (OS). MethodsThis study reports the findings of 67 patients with diffuse large B-cell lymphoma (DLBCL). These patients underwent interim whole-body dynamic 18F-FDG PET/CT scans from June 2021 to January 2023 at the Department of Nuclear Medicine, First Affiliated Hospital of Anhui Medical University. The predictive values of maximum standard uptake value (SUVmax), maximum of net glucose uptake rate (Kimax) and the predictive model combining Kimax and interim treatment response on the prognosis of patients was analyzed using receiver operating characteristic (ROC) curves. Kaplan-Meier survival curves and log-rank tests were used for survival analysis. Univariate and multivariate analyses were performed to screen for independent prognostic risk factors. ResultsAfter a median follow-up of 18 months, 21 patients (31.3%) experienced disease recurrence or death. The cut-off values for the SUVmax and the Kimax were 6.1 and 0.13 μmol min−1·ml−1, respectively. Ann Arbor stage, IPI, SUVmax, Kimax and interim treatment response were associated with PFS and OS in the univariate analysis. However, only Kimax and interim treatment response were independent influences on PFS and OS in multivariate analysis. ConclusionInterim whole-body dynamic 18F-FDG PET/CT Patlak imaging has significant prognostic value in patients with DLBCL. Among them, the interim dynamic parameter Kimax showed the best predictive value for prognosis compared with the interim SUVmax and interim treatment response. The predictive model established by Kimax and the interim treatment response allowed for the accurate stratification of the prognostic risk of DLBCL.

Association of single nucleotide variants in VEGFA and KDR with the risk and angiogenic features of diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype and dependent on angiogenesis (AG), whose main effectors are VEGFA and VEGFR2. Functional single nucleotide variants (SNVs) are described in VEGFA and KDR genes. However, it still unknown whether VEGFA − 2578C/A, −2489C/T, −1154G/A, −634G/C, −460C/T and KDR-604T/C, −271G/A, +1192G/A and +1719A/T SNVs act on DLBCL risk and angiogenic features. Genomic DNA from 168 DLBCL patients and 205 controls was used for SNV genotyping. Angiogenesis was immunohistochemically assessed in tumor biopsies, with reactions for VEGFA, VEGFR2, and CD34. VEGFA –1154GG genotype were associated with 1.6-fold higher DLBCL risk. KDR + 1192GG plus KDR + 1719 TT and KDR + 1192GG plus VEGFA − 2578CC combined genotypes are associated with 2.19- and 2.04-fold higher risks of DLBCL, respectively. VEGFA − 634GG or GC genotypes are associated with increased microvessel density and VEGFA levels. No relationship was observed between SNVs and cell-of-origin classification of DLBCL, but higher VEGFA and VEGFR2 were seen in non-germinal center tumors.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Background: Previous researches have mainly focused on the discussion of whether cancer stem cells exist in diffuse large B-cell lymphoma (DLBCL). However, some subgroups with dismal prognosis that exhibit stem cell-like characteristics have been overlooked. Methods: Using an innovative one-class logistic regression (OCLR) machine learning algorithm, we calculated stemness indices and systematically assessed their ability to reflect the oncogenic dedifferentiation-like characteristics of DLBCL. Next, we identified signatures associated with oncogenic dedifferentiation-like features and prognosis using LASSO and SVM-RFE algorithms and developed a proportional hazards model (Riskscore) for DLBCL through Cox regression. Then we stratified the risk of DLBCL (n = 2133) and evaluated the prognostic value of the risk model across known clinical and molecular subgroups. We further compared the characteristics of high- and low-risk DLBCL with Burkitt lymphoma. Finally, we investigated the mechanisms of poor prognosis in high-risk DLBCL using transcriptomics, genomics (n = 576) and single-cell RNA sequencing (n = 19) data, as well as cell experiments and internal validation cohorts. Results: In this study, we identified and validated a DLBCL subgroup (25.6% of DLBCL) with stem cell-like characteristics and dismal prognosis. This high-risk group was defined as polyamine metabolism-cold immune tumor with upregulated polyamine metabolic key enzyme (ODC1) and desert-like immune infiltration, and had a poor prognosis with lower 3-year OS rate (54.3% vs. 83.6%, p < 0.0001) and PFS rate (42.8% vs. 75.2%, p < 0.0001) compared to the low-risk group. We found that some patients with MYC rearrangement, double-hit, double-expresser, or complete remission may have either favorable or poor prognosis, which can be accurately identified by our risk stratification model. Additionally, the high-risk group exhibited malignant proliferative phenotypes similar to Burkitt lymphoma. Genomic analysis revealed widespread copy number losses in the chemokine and interferon coding regions 8p23.1 and 9p21.3 in the high-risk group. Bulk and single-cell transcriptome analysis indicated that the upregulation of ODC1 might mediate the cold immune microenvironment of DLBCL, and knocking down ODC1 effectively inhibited DLBCL cell proliferation. Promisingly, our model effectively identified patients who were insensitive to immunotherapy (CAR-T and immune checkpoint antibodies). The research was funded by: This work was supported by grants from the National Natural Science Foundation of China (grant no. 81873450, 82170181), Beijing Hospitals Authority Youth Programme (code: QML20200201), and Beijing Natural Science Foundation (No. 7222027) to Liang Wang. Keywords: Bioinformatics, Computational and Systems Biology, Microenvironment, Risk Models No conflicts of interests pertinent to the abstract.

A Decision-tree Approach to Stratify DLBCL Risk Based on Stromal and Immune Microenvironment Determinants.

A Decision-tree Approach to Stratify DLBCL Risk Based on Stromal and Immune Microenvironment Determinants.

A model to predict the prognosis of diffuse large B-cell lymphoma based on ultrasound images

The purpose of this paper was to assess the value of ultrasonography in the prognosis of diffuse large b-cell lymphoma (DLBCL) by developing a new prognostic model. One hundred and eleven DLBCL patients with complete clinical information and ultrasound findings were enrolled in our study. Univariate and multivariate regression analyses were used to identify independent risk factors for progression-free survival (PFS) and overall survival (OS). Receiver operator characteristic (ROC) curves were plotted and the corresponding area under the curve (AUC) was calculated to assess the accuracy of the international prognostic index (IPI) and new model in DLBCL risk stratification. The results suggested that hilum loss and ineffective treatment were independent risk variables for both PFS and OS in DLBCL patients. Additionally, the new model that added hilum loss and ineffective treatment to IPI had a better AUC for PFS and OS than IPI alone (AUC: 0.90, 0.88, and 0.82 vs. 0.71, 0.74, and 0.68 for 1-, 3-, and 5-year PFS, respectively; AUC: 0.92, 0.85 and 0.86 vs. 0.71, 0.75 and 0.76, for 1-, 3-, and 5-year OS, respectively). The model based on ultrasound images could better suggest PFS and OS of DLBCL, allowing for better risk stratification.

Association Between Polymorphism in Diabetes Susceptibility Gene Insulin-Like Growth Factor 2mRNA-Binding Protein 2 and Risk of Diffuse Large B-Cell Lymphoma.

Numerous studies have shown that polymorphisms in the diabetes susceptibility gene, insulin-like growth factor 2mRNA-binding protein 2 (IGF2BP2), are associated with the occurrence and development of various malignant tumors; however, their correlation with the onset of diffuse large B-cell lymphoma (DLBCL) is still unknown. Therefore, this study aimed to explore whether IGF2BP2 polymorphisms increase the risk of developing DLBCL. This study included 295 DLBCL patients and 331 healthy individuals. Peripheral blood was collected, and polymerase chain reaction-ligase detection reaction (PCR-LDR) was used to detect IGF2BP2 gene polymorphisms. Logistic regression was used to assess the association between IGF2BP2 polymorphism and the risk of DLBCL, adjusted for age, sex, and body mass index (BMI). P < .05 indicated statistical significance. The rs4402960 polymorphism in the IGF2BP2 gene was associated with the occurrence and development of DLBCL. After adjusting for age, sex, and BMI, GT (odd ratio [OR] = 1.54; 95% confidence interval [CI] = 1.08-2.19; P = .016), TT (OR = 2.00; 95% CI = 1.09-3.68; P = .026), and T genotype carrying (GT + TT) (OR = 1.62; 95% CI = 1.17-2.25; P = .004) significantly increased the risk of DLBCL. This study also found that the polymorphism rs1470579 was related to the development of DLBCL. After adjusting for age, sex, and BMI, AC (OR = 1.55; 95% CI = 1.11-2.17; P = .010), CC (OR = 2.18; 95% CI = 1.17-4.06; P = .014), and C genotype carrying (AC + CC) (OR = 1.64; 95% CI = 1.19-2.26; P = .002) significantly increased the risk of DLBCL. Our study found that polymorphism in the IGF2BP2 gene was associated with an increased risk of developing DLBCL.

Development and validation of a [18F]FDG PET/CT-based radiomics nomogram to predict the prognostic risk of pretreatment diffuse large B cell lymphoma patients

ObjectiveIn this study, based on PET/CT radiomics features, we developed and validated a nomogram to predict progression-free survival (PFS) for cases with diffuse large B cell lymphoma (DLBCL) treated with immunochemotherapy.MethodsThis study retrospectively recruited 129 cases with DLBCL. Among them, PET/CT scans were conducted and baseline images were collected for radiomics features along with their clinicopathological features. Radiomics features related to recurrence were screened for survival analysis using univariate Cox regression analysis with p < 0.05. Next, a weighted Radiomics-score (Rad-score) was generated and independent risk factors were obtained from univariate and multivariate Cox regressions to build the nomogram. Furthermore, the nomogram was tested for their ability to predict PFS using time-dependent receiver operating characteristic (ROC) curves, calibration curves, and decision curve analysis (DCA).ResultsBlood platelet, Rad-score, and gender were included in the nomogram as independent DLBCL risk factors for PFS. We found that the training cohort areas under the curve (AUCs) were 0.79, 0.84, and 0.88, and validation cohort AUCs were 0.67, 0.83, and 0.72, respectively. Further, the DCA and calibration curves confirmed the predictive nomogram’s clinical relevance.ConclusionUsing Rad-score, blood platelet, and gender of the DLBCL patients, a PET/CT radiomics-based nomogram was developed to guide cases’ recurrence risk assessment prior to treatment. The developed nomogram can help provide more appropriate treatment plans to the cases.Key Points• DLBCL cases can be classified into low- and high-risk groups using PET/CT radiomics based Rad-score.• When combined with other clinical characteristics (gender and blood platelet count), Rad-score can be used to predict the outcome of the pretreatment of DLBCL cases with a certain degree of accuracy.• A prognostic nomogram was established in this study in order to aid in assessing prognostic risk and providing more accurate treatment plans for DLBCL cases.

RAC1, a Potential Diagnostic and Prognostic Marker for Diffuse Large B Cell Lymphoma

The gene changes for diagnosis and prognosis of diffuse large B cell lymphoma (DLBCL) still remain unclear. RAC1 was reported to be asso;ciated with the B cell receptor signal pathway, but its relations with DLBCL have not yet been systematically explored. In this study, we have conducted molecular, bioinformatics and clinical analyses by using publicly available data from The Cancer Genome Atlas (TCGA). Wilcoxon signed-rank test and logistic regression were performed to evaluate the association between RAC1 and clinical features in patients. Kaplan-Meier and Cox regression methods were used to examine the impacts of RAC1 expression level on overall survival, and a nomogram was performed to illustrate the correlation between RAC1 and the risk of DLBCL. Our results revealed that the expression level of RAC1 in DLBCL was higher than that in normal tissues or lymphadenitis. High-level expression of RAC1 was significantly associated with clinical stage, as well as being an independent factor affecting overall survival. RAC1 was negatively correlated with Bruton's tyrosine kinase (BTK). The association between RAC1 gene expression and the risk of DLBCL was presented in a nomogram. In conclusion, RAC1 expression patterns may be used to predict the development and prognosis of DLBCL.

Comprehensive Analysis of TP53 and CD58 Mutations and Identification of Patients with Inferior Prognosis and Enhanced Immune Escape in Diffuse Large B Cell Lymphoma

Background: Studies on TP53 mutations as prognostic markers in diffuse large B-cell lymphoma (DLBCL) have historically been controversial and these results have not been consistent across different studies. Considering the complex pathophysiological mechanisms involved in DLBCL, we assumed that the interaction of TP53 with other genetic variants, which shape the discrepant immune landscape, could further promote the development of DLBCL, and thus be more prognostically predictive. Materials and methods: Comprehensive analysis of the genomic characteristics of TP53 and CD58 was performed through high-throughput DNA (n=176) and relevant RNA (n=152) sequencing in patients with de novo DLBCL. Mutation data of 1,001 DLBCL patients from Duke University's cohort were downloaded for validation. Another validation cohort was from REMoDL-B trail (N=400). Results: A total of 227 significantly mutated genes were identified, of which TP53 was the second most frequently mutated gene, with a rate of 30% (53 of 176) and 62 sequence variants detected. Among these variants, 74% were missense mutations, and the remaining were inactivating frameshift indels, nonsense mutations, coding sequencing indels and splicing mutations. Importantly, most mutations (87.5%) occurred in exons 5-8, which encoded the DBD region of TP53. Codons 175, 273, and 248 of the p53 protein had the highest mutation frequency. However, TP53 mutations alone are insufficient to effectively differentiate the risk of DLBCL, even when only considering mutations in the DBD region. We further found that DDX3X, MYLK2, and FUT6 mutations co-occurred with TP53 mutations, and CD58 mutations were mutually exclusive with TP53 mutations. No significant difference was observed in survival among those groups according to the combination of co-occurring mutation genes with TP53 (p=0.37 for DDX3X; p=0.11 for MYLK2; p=0.54 for FUT6). However, the combination of TP53 and CD58 mutations could significantly distinguish the prognosis of patients with DLBCL (p=0.033). Patients with both wild-type TP53 and CD58 had a better prognosis than patients with either of the two mutually exclusive modes of CD58 and TP53 mutations. Unexpectedly, patients with TP53 wild-type and CD58 mutations (TP53WT&CD58MUT) had worse survival than those with TP53 mutations and CD58 wild-type (TP53MUT&CD58WT). The relationship of a mutually exclusive mutant between CD58 and TP53 and the prognostic significance of this interaction was validated using publicly available data from 1,001 patients with DLBCL from the Duke university's cohort. We then explored whether the cooperation of the mutually exclusive mutations between TP53 and CD58 may profoundly influence the microenvironment in DLBCL. We found that the overall TMB was significantly higher in the TP53WT&CD58MUT group than in the TP53MUT&CD58WT group (p=0.0177), while there was no difference in TMB when dividing patients only according to TP53 mutation status (p=0.5348). In addition, the ESTIMATE immune scores in the TP53WT&CD58MUT group were significantly higher than that in the TP53MUT&CD58WT groups (p=0.0047). Moreover, the exhausted T cell, macrophage cell, NK cell, and Th1 cell enriched in the TP53WT&CD58MUT group. The difference between the two groups was mainly due to the combined influence of the mutation pattern 'TP53WT&CD58MUT', but rather only affected by the CD58 mutations, given the immune cell infiltration was similar when dividing patients just according to CD58 mutation status. Furthermore, the co-inhibitory receptors such as PD-1, TIM3, and LAG3 were preferentially expressed in the TP53WT&CD58MUT group. Inhibitory immunomodulators were also significantly upregulated in the TP53WT&CD58MUT group when comparing with the TP53WT&CD58WT group, suggesting the unique immune phenotype in the TP53WT&CD58MUT group. The findings that high immune scores and abundant infiltrating exhausted T cells in the TP53WT&CD58MUT group were validated in an independent external cohort from the REMoDL-B trail (N=400). GSEA showed significantly activated interferon-α and -γ responses and IL-6/JAK/STAT3 signaling in the TP53WT&CD58MUT group. Conclusions: Our findings suggest that TP53 mutation alone is insufficient to effectively differentiate the risk of DLBCL. The mutually exclusive patterns between TP53 and CD58 mutations accurately stratified patients with DLBCL to permit the optional immunotherapy. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A prospective analysis of red blood cell membrane polyunsaturated fatty acid levels and risk of non-Hodgkin lymphoma

Published studies report inconsistent associations of polyunsaturated fatty acid (PUFA) intake with non-Hodgkin lymphoma (NHL) risk. We conducted a nested case-control study in Nurses’ Health Study and Health Professionals Follow-Up Study participants to evaluate a hypothesis of inverse association of pre-diagnosis red blood cell (RBC) membrane PUFA levels with risk of NHL endpoints. We confirmed 583 NHL cases and matched 583 controls by cohort/sex, age, race and blood draw date/time. We estimated odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL endpoints using logistic regression. RBC PUFA levels were not associated with all NHL risk; cis 20:2n-6 was associated with follicular lymphoma risk (OR [95% CI] per one standard deviation increase: 1.35 [1.03–1.77]), and the omega-6/omega-3 PUFA ratio was associated with diffuse large B-cell lymphoma risk (2.33 [1.23–4.43]). Overall, PUFA did not demonstrate a role in NHL etiology; the two unexpected positive associations lack clear biologic explanations.

Abstract 741: Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin

Abstract Background: DLBCL is the most common non-Hodgkin lymphoma subtype in western countries and is clinically heterogeneous. Gene expression profiling has identified two major biologically distinctive DLBCL subtypes defined by their cell-of-origin (COO): germinal center B-cell (GCB) - characterized by BCL2 rearrangement and C-REL amplification, and activated B-cell (ABC) - characterized by constitutive activation of the NF-kB pathway. We evaluated putative DLBCL risk factors for etiologic heterogeneity as defined by COO. Methods: We used a clinic-based study of newly diagnosed NHL cases and frequency matched controls, enrolled from 2002-2014, with a total of 687 DLBCL cases and 2253 controls for this analysis. Using formalin-fixed, paraffin-embedded tumor tissue, we determined COO by either digital expression profiling (NanoString; classified as GCB, ABC, undetermined) or clinically using the Hans algorithm (immunohistochemical markers; classified as GCB, non-GCB, undetermined). Integrating these two sources of COO data, there were 271 GCB, 170 non-GCB, and 246 undetermined/missing (mainly due to lack of tissue) cases. Risk factor data were collected from self-administered questionnaires and included family history of hematologic malignancy; history of atopy, allergy, asthma, eczema, or autoimmune disease; blood transfusion; vaccination history; regular low-dose aspirin use; body mass index (BMI) 2 years prior diagnosis/enrollment; smoking history; alcohol consumption (never/current/former); leisure-time physical activity; and recreational sun exposure. Polytomous logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals for COO subtypes, adjusted for age, sex and residence. Results: The median age of cases was 64 years with 55% male; the median age of controls was 64 years and 53% male. The association with BMI (30+ vs. 18.5-24.9 kg/m2) was stronger for non-GCB (OR=2.21; 1.40-3.49) than for GCB (OR=1.70; 1.21-2.40) DLBCL (P-heterogeneity 0.02), while a family history of hematologic malignancy was associated with non-GCB (OR=2.27; 1.47-3.50) but not GCB (OR=1.30; 0.86-1.96) DLBCL, although the P-heterogeneity was not significant (P=0.13). For GCB, there was an inverse association with former (vs. never) alcohol use for GCB (OR=0.57; 0.39-0.83) but not for non-GCB (OR=0.98; 0.61-1.57) DLBCL (P-heterogeneity 0.007), and an inverse association with regular use of low-dose aspirin for GCB (OR=0.64; 0.47-0.87) but not for non-GCB (OR=0.88; 0.61-1.25) DLBCL (P-heterogeneity 0.05). No other risk factors evaluated showed important heterogeneity by COO. Conclusions: These initial results suggest most DLBCL risk factors do not show etiologic heterogeneity by DLBCL COO, although associations with BMI and family history with non-GCB DLBCL and alcohol and low-dose aspirin use with GCB DLBCL warrant follow-up. Citation Format: Geffen Kleinstern, Dennis P. Robinson, Lisa M. Rimsza, Melissa C. Larson, Rebecca L. King, Grzegorz S. Nowakowski, Carrie A. Thompson, Stephen M. Ansell, Matthew J. Maurer, Andrew L. Feldman, Susan L. Slager, Anne J. Novak, Thomas M. Habermann, James R. Cerhan. Evaluation of etiologic heterogeneity for risk of diffuse large B-cell lymphoma (DLBCL) subtype defined by cell-of-origin [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 741.