Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz

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Gewählte Publikation:

Troppan, K.
Molecular analysis of aggressive B-cell lymphomas
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] ; 2015. pp. [OPEN ACCESS]


Autor*innen der Med Uni Graz:
Prochazka Katharina
Deutsch Alexander
Neumeister Peter
Pichler Martin

Background: Diffuse large B cell lymphomas (DLBCL) are the most common occurring lymphoma worldwide. Despite recent efforts, their exact pathogenesis has not been elucidated yet. Micro-RNAs are short non-coding single-stranded RNA molecules regulating gene expression at the post-transcriptional level and their expression has been identified to correlate with tumor prognosis. Methods: For microRNA expression analysis real-time PCR on 81 samples was performed, including 63 DLBCL, and 18 controls, as well as on 4 lymphoma cell lines. Expression levels of a panel of 11 microRNAs that have been previously involved in other types of cancer were measured and correlated with clinical data. Furthermore, cell lines, lacking miR-199a and miR-497 expression, were electroporated with the two respective microRNAs and treated with standard immunochemotherapy routinely used in patients with DLBCL, followed by functional analyses including cell count and apoptosis assays. In a retrospective data analysis the inflammatory factors derived neutrophil to lymphocyte ratio (dNLR) and the C-reactive protein (CRP) have been evaluated regarding their prognostic explanatory power in a large cohort of DLBCL patients. Results: Seven microRNAs were statistically significant up-regulated in DLBCL compared to normal germinal center cells. However, high expression of miR-497 or miR-199a was associated with better overall survival (p=0.042 and p=0.007). Overexpression of miR-199a and miR-497 led to a statistically significant decrease in viable cells in a dose-dependent fashion after exposure to rituximab and various chemotherapeutics relevant in multi-agent lymphoma therapy. Furthermore, we could identify an independent significant association between high dNLR and high CRP levels with poor clinical outcome in multivariate analysis for overall survival (OS), as well as disease free survival (DFS). Conclusion: Our data indicate that elevated miR-199a and miR-497 levels are associated with improved survival in DLBCL patients most likely by modifying drug sensitivity to immunochemotherapy. This functional impairment may serve as a potential novel therapeutic target in future treatment. We could further show that a high dNLR or a high CRP value at diagnosis of DLBCL represent an independent poor prognostic factor for clinical outcome. Our data encourages the further validation of these easily available parameters in prospective studies and as a potential stratification tool in clinical trials.

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