Circulating microRNAs in Cerebrospinal Fluid and Plasma: Sensitive Tool for Detection of Secondary CNS Involvement, Monitoring of Therapy and Prediction of CNS Relapse in Aggressive B-NHL Lymphomas

SIMPLE SUMMARY: Lymphoma involving the central nervous system and CNS relapse present diagnostic and predictive challenges. Its diagnosis is based on conventional methods with low sensitivity and/or specificity. More powerful tools for its early detection, response evaluation, and CNS relapse prediction are needed. MicroRNAs are short post-transcriptional gene regulators that are remarkably stable and detectable extracellularly in body fluids. We evaluated the diagnostic and predictive potential of circulating oncogenic microRNAs (oncomiRs) in CSF and plasma for the detection of secondary CNS involvement in aggressive B-NHL lymphomas, as well as for detection and prediction of their CNS relapse. Our findings indicate that the evaluation of oncogenic microRNAs in CSF and plasma potentially provides a sensitive tool for the early detection of secondary CNS lymphoma, the monitoring and estimating of treatment efficacy, and the prediction and early detection of CNS relapse. ABSTRACT: Lymphoma with secondary central nervous system (CNS) involvement represents one of the most aggressive malignancies, with poor prognosis and high mortality. New diagnostic tools for its early detection, response evaluation, and CNS relapse prediction are needed. We analyzed circulating microRNAs in the cerebrospinal fluid (CSF) and plasma of 162 patients with aggressive B-cell non-Hodgkin’s lymphomas (B-NHL) and compared their levels in CNS-involving lymphomas versus in systemic lymphomas, at diagnosis and during treatment and CNS relapse. We identified a set of five oncogenic microRNAs (miR-19a, miR-20a, miR-21, miR-92a, and miR-155) in CSF that detect, with high sensitivity, secondary CNS lymphoma involvement in aggressive B-NHL, including DLBCL, MCL, and Burkitt lymphoma. Their combination into an oncomiR index enables the separation of CNS lymphomas from systemic lymphomas or nonmalignant controls with high sensitivity and specificity, and high Receiver Operating Characteristics (DLBCL AUC = 0.96, MCL = 0.93, BL = 1.0). Longitudinal analysis showed that oncomiR levels reflect treatment efficacy and clinical outcomes, allowing their monitoring and prediction. In contrast to conventional methods, CSF oncomiRs enable detection of early and residual CNS involvement, as well as parenchymal involvement. These circulating oncomiRs increase 1–4 months before CNS relapse, allowing its early detection and improving the prediction of CNS relapse risk in DLBCL. Similar effects were detectable, to a lesser extent, in plasma.