PATH-10. MicroRNAs AS PREDICTORS FOR CNS RELAPSE OF SYSTEMIC DIFFUSE LARGE B-CELL LYMPHOMA

Diffuse large B-cell lymphoma (DLBCL) represents a heterogeneous group of tumors with a high variance of genetic abnormalities, clinical features, response to treatment and prognosis. Systemic DLBCL is a potentially curable disease using current regimen of immunochemotherapy. Central nervous system (CNS) relapse is a complication that occurs in up to 7% of DLBCL patients and is associated with a high fatality rate. Early identification of molecular markers for CNS involvement may serve for the highly needed accurate stratification of patients into risk groups regarding CNS relapse. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression at the post-transcriptional level and are known to be involved in DLBCL pathophysiology. We utilized miRNA multiplex reading of systemic DLBCL samples with and without CNS relapse and detected two differentially expressed miRNAs, miR-20a and miR-30d, that predict for CNS involvement. Replication of these results in different samples was used for validation. MiR-20a belongs to the miR-17-92 cluster, and was shown to suppress apoptosis, and to promote cell proliferation, survival and tumorigenesis. MiR-20a was found to be upregulated in PCNSL compared to nodal DLBCL, possibly pointing on its involvement in CNS rooting. MiR-30d has been demonstrated to act as an oncogene in medulloblastoma, hepatocellular carcinoma and prostate cancer. It is possible that miR-30d contributes to the propensity of subsets of DLBCL to spread into the CNS since it is associated with regulation of cell proliferation and metastases. Bioinformatics miRNA-target enrichment analysis revealed a number of putative mechanisms for these miRNAs regulation of CNS relapse, including neuronal plasticity and WNT signaling pathway. Both mechanisms were described as partly responsible for continued tumor growth and recurrence in glioblastoma and secondary CNS tumors and may have a similar role in the unique properties of DLBCL clones that expand, spread and proliferate in the CNS.