Dataset Information

Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma.

ABSTRACT: MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL), where they reflect the malignant B-cells and the immune infiltrate within the tumor microenvironment. There remains a paucity of data in DLBCL regarding cell-free (c-f) miRNA as disease response biomarkers. Immunosuppressive monocyte/macrophages, which are enriched in DLBCL, are disease response markers in DLBCL, with miRNA key regulators of their immunosuppressive function. Our aim was to determine whether plasma miRNA that reflect the activity of the malignant B-cell and/or immunosuppressive monocytes/macrophages, have value as minimally-invasive disease response biomarkers in DLBCL. Quantification of 99 DLBCL tissues, to select miRNA implicated in immunosuppressive monocytes/macrophage biology, found miR-494 differentially elevated. In a discovery cohort (22 patients), pre-therapy c-f miR-494 and miR-21 but not miR-155 were raised relative to healthy plasma. Both miR-494 and miR-21 levels 3-6 months reduced post immuno-chemotherapy. The validation cohort (56 patients) was from a prospective clinical trial. Interestingly, in sequential samples both miRNAs decreased in patients becoming Positron Emission Tomography/Computerized Tomography (PET/CT)-ve, but not in those remaining interim-PET/CT+. Patient monocytes were phenotypically and functionally immunosuppressive with ex-vivo monocyte depletion enhancing T-cell proliferation in patient but not healthy samples. Pre-therapy monocytes showed an immunosuppressive transcriptome and raised levels of miR-494. MiR-494 was present in all c-f nanoparticle fractions but was most readily detectable in unfractionated plasma. Circulating c-f miR-494 and miR-21 are disease response biomarkers with differential response stratified by interim-PET/CT in patients with DLBCL. Further studies are required to explore their manipulation as potential therapeutic targets.

SUBMITTER: Cui Q

PROVIDER: S-EPMC6205167 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma.

Cui Qingyan Q Vari Frank F Cristino Alexandre S AS Salomon Carlos C Rice Gregory E GE Sabdia Muhammed B MB Guanzon Dominic D Palma Carlos C Mathew Marina M Talaulikar Dipti D Jain Sanjiv S Han Erica E Hertzberg Mark S MS Gould Clare C Crooks Pauline P Thillaiyampalam Gayathri G Keane Colm C Gandhi Maher K MK

Oncotarget 20181005 78

MicroRNA (miRNA)s are dysregulated in Diffuse large B-cell lymphoma (DLBCL), where they reflect the malignant B-cells and the immune infiltrate within the tumor microenvironment. There remains a paucity of data in DLBCL regarding cell-free (c-f) miRNA as disease response biomarkers. Immunosuppressive monocyte/macrophages, which are enriched in DLBCL, are disease response markers in DLBCL, with miRNA key regulators of their immunosuppressive function. Our aim was to determine whether plasma miRNA ...[more]

PMID: 30410665

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Project description:Background18F-fluorodeoxyglucose (18F-FDG) positron emission tomography-computed tomography (PET-CT) has been used in response evaluation systems for malignant lymphomas and is an important tool for determining efficacy and prognosis. The Deauville 5-point scale (D-5PS) is an 18F-FDG PET-CT image-interpretation protocol for patients with lymphoma. Nevertheless, a number of limitations in visual image interpretation, such as interobserver disagreement and the increase of false-positive results, suggests that new parameters are needed. In this study, we aimed to evaluate the prognostic values of interim-treatment (I-) and end-of-treatment (EOT) PET-CT by comparing D-5PS to the semiquantitative lesion-to-liver maximum standardized uptake value ratio (RLL).MethodsA total of 90 patients with diffuse large B-cell lymphoma (DLBCL) (45 I-PET and 45 EOT-PET) were analyzed, and the RLL was calculated. Patients were additionally evaluated using the D-5PS system. We determined the optimal cutoff value of RLL using receiver operating characteristic (ROC) analysis. Kaplan-Meier survival analysis was used to compare the outcome predictions, while multivariate Cox regression analysis was used to identify the predictive factors.ResultsAmong the patients examined, 41 (20 I-PET and 21 EOT-PET) experienced progression, and 49 (25 I-PET, 24 EOT-PET) did not. The optimal cutoff values of the RLL for predicting disease progression were 1.37 for I-PET (sensitivity 75%, specificity 88%) and 2.03 for EOT-PET (sensitivity 45.5%, specificity 100%), while the cutoffs of the D-5PS were scores 4 for I-PET (sensitivity 80%, specificity 72%) and 5 for EOT-PET (sensitivity 40.9%, specificity 100%). The prognostic efficacy was higher for the RLL at interim than for the D-5PS [area under the curve (AUC) =0.848 vs. 0.741]. The EOT prognostic efficacy of both evaluation methods was essentially equivalent (AUC =0.785 vs. 0.725). Univariate and multivariate analyses showed that RLL and D-5PS were independent factors affecting DLBCL outcomes for both interim and EOT assessment.ConclusionsRLL and D-5PS have independent predictive values for the interim and EOT evaluation of outcomes in patients with DLBCL. The RLL has better interim predictive ability than does D-5PS and can optimize D-5PS interpretation, thus improving interim outcome prediction.

Project description:Fluorine-18-fluoro-2-deoxy-D-glucose (FDG) is widely used as positron-emission-tomography (PET) radiotracer for the detection and staging of human cancer. Tumor uptake of FDG varies substantially between different cancer types and between patients with the same tumor type. The molecular basis for this heterogeneity is unknown. Using cancer cell lines and primary human tumors of distinct histologic origins, we here show that increased FDG uptake is universally associated with coordinate upregulation of genes within the glycolysis, pentose-phosphate, and other related metabolic pathways. In primary human breast cancers, this FDG signature shows significant overlap with established breast cancer signatures for the “basal-like” disease subtype and “poor prognosis”. FDG high breast cancer showed significantly more gene copy number alterations genome wide than FDG low cancers. About 50 % of primary breast cancers with high FDG uptake and FDG gene expression signature show DNA copy gain encompassing the c-myc gene locus and express gene sets regulated by the transcription factor MYC. Our data shows that FDG-PET marks a distinct subset of “basal-like” human breast cancer which is characterized by MYC and prognostically unfavorable gene expression signatures, suggesting that FDG-PET imaging may be useful to risk-stratify patients with locally advanced breast cancer. Our general strategy to identify molecular determinants of FDG-retention through a genome-wide approach consisted of FDG uptake measurements in cancer cell lines and primary human tumors, the selection of samples with particularly high versus low FDG-retention, and subsequent pathway-based analysis of RNA expression data collected from these samples. Cell line RNA was extracted from a 10 cm plate seeded simultaneously and at the same density as the wells for FDG-uptake assays. For primary human tumor samples, RNA was extracted from macrodissected frozen tumor tissue. All cell line RNA samples and the astrocytoma RNA aliquots were hybridized to Affymetrix U133 Plus 2.0 arrays. All primary breast cancer RNA samples were hybridized to Affymetrix U133A arrays.

Dataset Information

Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma.

Publications

Circulating cell-free miR-494 and miR-21 are disease response biomarkers associated with interim-positron emission tomography response in patients with diffuse large B-cell lymphoma.

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