Advanced Classical Hodgkin Lymphoma new insights in prognostic factors using gene and microRNA expression signatures

Resumen

Classical Hodgkin lymphoma (cHL) is assumed to be a curable tumor, but an important fraction of patients with advanced disease do not respond favorably to the standard chemotherapy regimens based on adriamycin and current predictive systems, based on clinical and analytical parameters, fail to accurately identify these high risk patients. Thus, the identification of biomarkers associated with treatment response remains a critical challenge in this lymphoid malignancy. cHL represents a distinctive model of histological complexity, with a minor population of the characteristic tumor cells, the Hodgkin and Reed Sternberg cells (HRS) diluted in a complex reactive inflammatory background. The intrinsic relationship between the HRS cells and their microenvironment is only partially understood but important advances in the understanding of the cHL pathophysiology are being made. Indeed, microarray expression studies of tumor samples have led to the identification of signatures and biological processes associated to Hodgkin¿s lymphoma pathogenesis and treatment response, showing that outcome in cHL patients could be related with both biological characteristic components of cHL tumors. However, no steps towards the translation of gene profiling results into routine clinical practice have been made. This study identified gene subsets expressed either by the tumoral HRS cells and the Hodgkin¿s microenvironment showing that robust methodologies based on quantitative realtime-PCR- (RT-PCR) assays are suitable for expression profiling of tumors and can be easily applied to paraffin-embedded samples. By a sequential analysis process, functional gene signatures associated with treatment response were first identified and finally a quantitative RT-PCR assay for patients with advanced cHL was described, incorporating a limited number of genes and pathways from tumor and microenvironment cell components, designed for application to routine formalin-fixed paraffin-embedded samples. This model was able to identify patient subgroups with highly different probabilities of treatment failure. Additionally, it was able to incorporate one of the well established clinical variables (Stage IV), thus integrating the main biological and molecular characteristics of the tumors related with treatment response and the tumor burden estimation in a single scoring system. MicroRNAs (miRNAs) have been described to be essential regulators of cell differentiation and biological processes, emerging as robust predictor and prognostic markers. Specific signatures from the HRS cells and their microenvironment have been proposed, but the potential prognostic role of them remains unclear. Thus, this study additionally investigated whether miRNA signatures could allow to a better understanding of cHL pathogenesis and identified a cHL miRNA signature related to treatment response.