MiR-150 is a negative independent prognostic biomarker for primary gastrointestinal diffuse large B-cell lymphoma.
ABSTRACT: A number of studies suggest an association between miRNAs and diffuse large B-cell lymphoma (DLBCL). The present study aimed to investigate the prognostic value of microRNA (miR-150) in primary gastrointestinal (PGI)-DLBCL, by assessing the association between miR-150 expression and clinicopathological characteristics in patients with PGI-DLBCL. A total of 84 patients diagnosed with PGI-DLBCL were recruited and both tumor and adjacent non-tumor tissue samples were collected. miR-150 expression was assessed via reverse transcription-quantitative (RT-q)PCR analysis. The results demonstrated that miR-150 expression was significantly lower in PGI-DLBCL tissues compared with adjacent non-tumor tissues. Furthermore, receiver operating characteristic (ROC) curve analysis indicated that the optimal cut-off value of miR-150 for predicting survival was 8.965 with high sensitivity (79.8%) and specificity (77.1%). Patients were divided into two groups according to this cut-off value, as follows: High (n=18) and low expression (n=66) groups. Low miR-150 expression was significantly associated with clinical stage, International Prognostic Index (IPI), Eastern Cooperative Oncology Group status and use of rituximab. RT-qPCR analysis demonstrated that miR-150 expression was significantly lower in patients with high IPI scores compared with patients with low IPI scores. Downregulated miR-150 expression was significantly associated with shorter overall survival (OS) time and progression-free survival (PFS) time in patients with PGI-DLBCL. Furthermore, miR-150 level and IPI score were identified as two risk factors for OS and PFS. The diagnostic value of miR-150 was evaluated via ROC curve analysis, with an area under the curve value of 0.882. Taken together, the results of the present study suggest that miR-150 is a potential diagnostic marker of PGI-DLBCL, and may also serve as a useful prognostic factor for survival outcomes in patients with PGI-DLBCL.
Project description:Primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL) is a highly heterogeneous type of non-Hodgkin lymphoma. A number of studies have demonstrated that microRNA-130a (miR-130a) serves a role in the tumorigenesis and prognosis of numerous human tumors. However, to the best of our knowledge, the prognostic significance of miR-130a in PGI-DLBCL remains unknown. The present study explored the association between miR-130a and the clinical outcomes of PGI-DLBCL. Relative miR-130a expression was assessed by reverse transcription-quantitative PCR. Immunohistochemistry was used to detect expression levels of BCL-2, c-MYC, neprilysin, B-cell lymphoma 6 protein, PWWP domain-containing DNA repair factor 3A and proliferation marker protein Ki-67. A receiver operating characteristic curve was constructed to analyze the specificity and sensitivity of microRNA levels in the diagnosis of PGI-DLBCL. Survival curves were constructed using the Kaplan-Meier method. In the present study, miR-130a expression was notably higher in patients with PGI-DLBCL compared with in the controls (P<0.0001). miR-130a overexpression was closely associated with a high International Prognostic Index score (3–5) and drug resistance (P=0.017 and P=0.044, respectively). No significant difference in other clinical features was observed. Patients with increased expression levels of miR-130a had lower overall survival [hazard ratio (HR), 2.998; 95% CI, 1.347-6.673; P=0.007] and progression-free survival (HR, 3.325; 95% CI, 1.488-7.429; P=0.003) compared with patients who had lower expression levels of miR-130a. Furthermore, multivariate Cox regression analysis suggested that miR-130a was a negative prognostic parameter in PGI-DLBCL. Therefore, upregulation of miR-130a could become a potential prognostic marker for PGI-DLBCL. Additionally, further study of these results may have important guiding significance for the prognosis of patients with PGI-DLBCL in the clinical setting.
Project description:BACKGROUND:Treatment resistance is a major clinical challenge of diffuse large B-cell lymphoma (DLBCL) where approximately 40% of the patients have refractory disease or relapse. Since DLBCL is characterized by great clinical and molecular heterogeneity, the purpose of the present study was to investigate whether miRNAs associated to single drug components of R-CHOP can improve robustness of individual markers and serve as a prognostic classifier. METHODS:Fifteen DLBCL cell lines were tested for sensitivity towards single drug compounds of the standard treatment R-CHOP: rituximab (R), cyclophosphamide (C), doxorubicin (H), and vincristine (O). For each drug, cell lines were ranked using the area under the dose-response curve and grouped as either sensitive, intermediate or resistant. Baseline miRNA expression data were obtained for each cell line in untreated condition, and differential miRNA expression analysis between sensitive and resistant cell lines identified 43 miRNAs associated to growth response after exposure towards single drugs of R-CHOP. Using the Affymetrix HG-U133 platform, expression levels of miRNA precursors were assessed in 701 diagnostic DLBCL biopsies, and miRNA-panel classifiers predicting disease progression were build using multiple Cox regression or random survival forest. Classifiers were validated and ranked by repeated cross-validation. RESULTS:Prognostic accuracies were assessed by Brier Scores and time-varying area under the ROC curves, which revealed better performance of multivariate Cox models compared to random survival forest models. The Cox model including miR-146a, miR-155, miR-21, miR-34a, and miR-23a~miR-27a~miR-24-2 cluster performed the best and successfully stratified GCB-DLBCL patients into high- and low-risk of disease progression. In addition, combination of the Cox miRNA-panel and IPI substantially increased prognostic performance in GCB classified patients. CONCLUSION:As a proof of concept, we found that expression data of drug associated miRNAs display prognostic utility and adding these to IPI improves prognostic stratification of GCB-DLBCL patients treated with R-CHOP.
Project description:Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of lymphoma, with different clinical manifestation and prognosis. The International Prognostic Index (IPI), an index designed during the prerituximab era for aggressive lymphoma, showed variable values in the prediction of patient clinical outcomes. The aim of this study was to analyze the prognostic value and causes of pretreatment liver injury in 363 de novo DLBCL patients in our institution. Pretreatment liver impairment, commonly detected in lymphoma patients, showed significant association with poor outcomes and increased serum inflammatory cytokines in DLBCL patients but had no relation to hepatitis B virus replication nor lymphomatous hepatic infiltration. Multivariate analysis revealed that liver dysfunction, advanced Ann Arbor stage, and elevated lactate dehydrogenase (LDH) were independent adverse prognostic factors of both PFS and OS. Accordingly, a new liver-IPI prognostic model was designed by adding liver injury as an important factor in determining IPI score. Based on Kaplan-Meier curves for PFS and OS, the liver-IPI showed better stratification in DLBCL patients than either the IPI or the revised IPI in survival prediction.
Project description:PURPOSE:Diffuse large B-cell lymphoma (DLBCL) heterogeneity has prompted investigations for new biomarkers that can accurately predict survival. A previously reported 6-gene model combined with the International Prognostic Index (IPI) could predict patients' outcome. However, even these predictors are not capable of unambiguously identifying outcome, suggesting that additional biomarkers might improve their predictive power. EXPERIMENTAL DESIGN:We studied expression of 11 microRNAs (miRNA) that had previously been reported to have variable expression in DLBCL tumors. We measured the expression of each miRNA by quantitative real-time PCR analyses in 176 samples from uniformly treated DLBCL patients and correlated the results to survival. RESULTS:In a univariate analysis, the expression of miR-18a correlated with overall survival (OS), whereas the expression of miR-181a and miR-222 correlated with progression-free survival (PFS). A multivariate Cox regression analysis including the IPI, the 6-gene model-derived mortality predictor score and expression of the miR-18a, miR-181a, and miR-222, revealed that all variables were independent predictors of survival except the expression of miR-222 for OS and the expression of miR-18a for PFS. CONCLUSION:The expression of specific miRNAs may be useful for DLBCL survival prediction and their role in the pathogenesis of this disease should be examined further.
Project description:Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and displays heterogeneous clinical and molecular characteristics. In this study, high throughput gene expression profiling of DLBCL tumor samples was used to design a 12-gene expression-based risk score (GERS) predictive for patient's overall survival. GERS allowed identifying a high-risk group comprising 46,4% of the DLBCL patients in two independent cohorts (n=414 and n=69). GERS was shown to be an independent predictor of survival when compared to the previously published prognostic factors, including the International Prognostic Index (IPI). GERS displayed a prognostic value in germinal-center B-cell-like subgroup (GCB) and activated B cell-like (ABC) molecular subgroups of patients as well as in DLBCL patients treated with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) or rituximab-CHOP (R-CHOP) regimens. Combination of GERS and IPI lead to a potent prognostic classification of DLBCL patients. Finally, a genomic instability gene signature was highlighted in gene expression profiles of patients belonging to the high-risk GERS-defined group.
Project description:The prognostic value of CD30 expression in diffuse large B-cell lymphoma (DLBCL)remains controversial. Herein, we performed this retrospective study to investigate the clinical and prognostic significance of CD30 expression in patients with DLBCL.Among all the 146 patients, the expression of CD30 was observed in 23 cases (15.7%).The DLBCL patients with CD30 expression showed more likely to present B symptoms, bone marrow involvement, non-germinal centre B-cell-like (Non-GCB) DLBCL, BCL-2 and Ki-67 overexpression (p<0.05). Patients with CD30 expression showed significantly poor overall and event-free survival compared with CD30 negative patients(p = 0.031 and 0.041, respectively), especially those with the high intermediate/high-risk international prognostic index (IPI)(p = 0.001 and 0.007, respectively). The prognostic value of CD30 expression retained in DLBCL patients treated with either CHOP (cyclophosphamide, doxorubicin, vincristine,prednisone) or R-CHOP(rituximab+CHOP). The multivariate analysis revealed that the expression of CD30 remained an unfavorable factor for both overall and event-free survival (p = 0.001 and 0.002, respectively). In conclusion, these data suggest that CD30 is expressed predominantly in Non-GCBDLBCL. The expression of CD30 implied poor outcome in DLBCL patients treated with either CHOP or R-CHOP, especially those with the high intermediate/high-risk IPI, possibly indicating that anti-CD30 monoclonal antibody could be of clinical interest.
Project description:Several gene-expression signatures predict survival in diffuse large B-cell lymphoma (DLBCL), but the lack of practical methods for genome-scale analysis has limited translation to clinical practice. We built and validated a simple model using one gene expressed by tumor cells and another expressed by host immune cells, assessing added prognostic value to the clinical International Prognostic Index (IPI). LIM domain only 2 (LMO2) was validated as an independent predictor of survival and the "germinal center B cell-like" subtype. Expression of tumor necrosis factor receptor superfamily member 9 (TNFRSF9) from the DLBCL microenvironment was the best gene in bivariate combination with LMO2. Study of TNFRSF9 tissue expression in 95 patients with DLBCL showed expression limited to infiltrating T cells. A model integrating these 2 genes was independent of "cell-of-origin" classification, "stromal signatures," IPI, and added to the predictive power of the IPI. A composite score integrating these genes with IPI performed well in 3 independent cohorts of 545 DLBCL patients, as well as in a simple assay of routine formalin-fixed specimens from a new validation cohort of 147 patients with DLBCL. We conclude that the measurement of a single gene expressed by tumor cells (LMO2) and a single gene expressed by the immune microenvironment (TNFRSF9) powerfully predicts overall survival in patients with DLBCL.
Project description:<h4>Background</h4>Elevated red blood cell distribution width (RDW) and decreased platelet count (PLT) can be clinically relevant to the prognosis in cancer patients. However, their prognostic values in patients with diffuse large B-cell lymphoma (DLBCL) need to be further explored.<h4>Methods</h4>Healthy donors (n?=?130) and patients with DLBCL (n?=?349) were included and evaluated retrospectively in this study. The prognostic influence of clinical and pathological factors including RDW and PLT on overall survival (OS) and progression-free survival (PFS) were studied by Kaplan-Meier curves. To evaluate the independent prognostic relevance of RDW and PLT, univariate and multivariate Cox proportional hazards regression models were applied. The adjusted IPI model was established based on the results of multivariate analysis, and verified by Harrell's C statistical analysis.<h4>Results</h4>Kaplan-Meier curves indicated that an elevated RDW value and thrombocytopenia are poor factors for OS (P?<?0.001, P?=?0.006) and PFS (P?=?0.003, P?<?0.001) in DLBCL patients. Multivariate analysis confirmed that elevated RDW value (HR?=?2.026, 95%CI?=?1.263-3.250, P?=?0.003) and decreased PLT count (HR =1.749, 95%CI?=?1.010-3.028, P?=?0.046) were both independent prognostic factors. The c-index of IPI and NCCN-IPI were increased when RDW level and PLT were supplemented in our cohort.<h4>Conclusions</h4>Our study shows that elevated RDW level and decreased PLT are independent poor prognostic factors in newly diagnosed DLBCL patients. Adding RDW and PLT to the IPI score may improve its predictive ability, and the adjusted IPI may be more powerful in predicting the survival of DLBCL patients in the rituximab era.
Project description:The international prognostic index (IPI) and similar models form the cornerstone of clinical assessment in newly diagnosed diffuse large B-cell lymphoma (DLBCL). While being simple and convenient to use, their inadequate use of the available clinical data is a major weakness. In this study, we compared performance of the International Prognostic Index (IPI) and its variations (R-IPI and NCCN-IPI) to a Cox proportional hazards (CPH) model using the same covariates in nondichotomized form. All models were tested in 4863 newly diagnosed DLBCL patients from population-based Nordic registers. The CPH model led to a substantial increase in predictive accuracy as compared to conventional prognostic scores when evaluated by the area under the curve and other relevant tests. Furthermore, the generation of patient-specific survival curves rather than assigning patients to one of few predefined risk groups is a relevant step toward personalized management and treatment. A test-version is available on lymphomapredictor.org.
Project description:Kinesin family member 2A (KIF2A), a conserved motor protein, plays a critical role in the pathogenesis and prognosis of several malignant tumors. The aim of the present study was to investigate KIF2A expression in diffuse large B cell lymphoma (DLBCL), evaluate the association between KIF2A expression and the clinical parameters of the disease, and determine its prognostic value. KIF2A expression was evaluated in 134 DLBCL and 57 reactive hyperplasia samples using immunohistochemistry on a tissue microarray. The correlations between KIF2A expression with clinical parameters and prognosis were estimated using univariate and multivariate analyses. The expression of KIF2A was significantly higher in DLBCL tissue samples compared with those from subjects with reactive hyperplasia (P=0.002). Furthermore, increased expression of KIF2A protein in DLBCL was related to Ann Arbor stage (P=0.027) and international prognostic index (IPI) score (P=0.01). The survival analysis showed that KIF2A expression (P=0.016), serum LDH level (P=0.049), and IPI score (P<0.001) were independent prognostic markers for DLBCL. Our findings also confirmed that downregulating KIF2A expression decreased tumor cell viability, accompanied by downregulation of pAKT levels. Taken together, these data provide the first evidence that increased KIF2A expression predicts poor prognosis in patients with DLBCL, and a rationale for treatment of DLBCL by targeting KIF2A.