Abstract
BackgroundDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment.MicroRNAs (miRNAs) are under investigation as novel diagnostic and prognostic biomarkers in several malignancies, including malignant lymphomas. While tissue miRNAs in DLBCL patients have been extensively studied as biomarkers, only few reports to date have evaluated the role of circulating/serum miRNAs as potential prognostic factors.Here circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients.MethodsMiRNAs were selected by global expression profile of serum miRNAs of DLBCL patients, The Cancer Genome Atlas (TCGA) analysis and literature research.Serum and tissues miRNA expression profile in de novo DLBCL patients, consecutively enrolled for this study, were detected by quantitative real-time polymerase chain reaction. Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher’s exact test. Survival analysis was conducted through the use of Kaplan-Meier method. Spearman’s Rho was applied to study the correlation between miRNA distributions and days to first relapse.Experimentally validated miRNA-target interactions were assessed by miRTarBase database. Negative miRNA-mRNA correlation was evaluated in TCGA DLBCL dataset. Pathway analysis was performed by the functional annotation clustering DAVID tool.ResultsWe showed a significant modulation of serum miR-22 after R-CHOP treatment compared with basal values but no difference between baseline serum miRNAs values of DLBCL patients and healthy controls. High expression level of serum miR-22 in DLBCL at diagnosis (n = 36) is associated with a worse PFS and is independent of the currently used clinical prognostic index. Integrative and pathways analysis of miR-22 identified target genes involved in different important pathways such as p53 signaling.ConclusionsOur data suggest that miR-22 is of potential interest as non-invasive biomarker to predict clinical outcome in DLBCL patients. Characterization of miR-22 pathways can pave the way to the development of targeted therapy approaches for specific subgroups of DLBCL patients.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult
We showed a significant modulation of serum miR-22 after R-CHOP treatment compared with basal values but no difference between baseline serum miRNAs values of DLBCL patients and healthy controls
Study objectives The objectives of the study were: i) to evaluate the difference in miRNAs expression at diagnosis and after RCHOP therapy in serum of DLBCL patients; ii) to evaluate the correlation between circulating miRNA and response to treatment; iii) to find a specific miRNA signature significantly related to clinical outcome of patients in terms of Progression-Free Survival (PFS); iv) to investigate the correlation between circulating miRNAs and other baseline clinicalbiological factors [gender, median age, Ann Arbor stage, International Prognostic Index (IPI), lactate dehydrogenase (LDH) value, cell of origin, presence of Bcl2, Bcl6 and Myc rearrangements]
Summary
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients. Diffuse large B-cell lymphoma (DLBCL), the most common high-grade non-Hodgkin lymphoma, is a heterogeneous group of tumors with aggressive clinical course [1]. Their heterogeneity makes prognostication and choice of treatment strategy difficult [2]. Immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment [3] With this therapeutic approach up to 40% of patients experience early treatment failure or relapse after initial response [4]. DLBCL heterogeneity and the current lack of reliable predictors have prompted investigations for new biomarkers that can accurately predict survival [12]
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