Abstract
Despite major advances in the treatment of classic Hodgkin's lymphoma (cHL), approximately 30% of patients in advanced stages may eventually die as result of the disease, and current methods to predict prognosis are rather unreliable. Thus, the application of robust techniques for the identification of biomarkers associated with treatment response is essential if new predictive tools are to be developed. We used gene expression data from advanced cHL patients to identify transcriptional patterns from the tumoral cells and their nonneoplastic microenvironment, associated with lack of maintained treatment response. Gene-Set Enrichment Analysis was used to identify functional pathways associated with unfavorable outcome that were significantly enriched in either the Hodgkin's and Reed-Sternberg cells (regulation of the G2-M checkpoint, chaperones, histone modification, and signaling pathways) or the reactive cell microenvironment (mainly represented by specific T-cell populations and macrophage activation markers). To explore the pathways identified previously, we used a series of 52 formalin-fixed paraffin-embedded advanced cHL samples and designed a real-time PCR-based low-density array that included the most relevant genes. A large majority of the samples (82.7%) and all selected genes were analyzed successfully with this approach. The results of this assay can be combined in a single risk score integrating these biological pathways associated with treatment response and eventually used in a larger series to develop a new molecular outcome predictor for advanced cHL.
Highlights
Despite major advances in the treatment of classic Hodgkin’s lymphoma, f30% of patientsinadvancedstagesmayeventuallydieasresultof the disease,andcurrentmethods topredict prognosis are ratherunreliable.the applicationof robust techniques for theidentificationofbiomarkers associated with treatment response is essentialif new predictive tools are to be developed
This study identifies gene subsets expressed by the tumoral cells and the Hodgkin’s microenvironment and shows that robust methodologies based on quantitative real-time PCR are suitable for expression profiling of tumors and can be applied to paraffin-embedded samples allowing interrogating a limited number of selected genes in a single sample
Established classic Hodgkin’s lymphoma (cHL)-derived cell lines are commonly used as model systems for characterizing the biology of Hodgkin’s and Reed-Sternberg (HRS) cells, whereas tumoral samples represent a complex mixture of tumoral cells and reactive microenvironment [34]
Summary
Despite major advances in the treatment of classic Hodgkin’s lymphoma (cHL), f30% of patientsinadvancedstagesmayeventuallydieasresultof the disease,andcurrentmethods topredict prognosis are ratherunreliable.the applicationof robust techniques for theidentificationofbiomarkers associated with treatment response is essentialif new predictive tools are to be developed. Current predictive systems are based on clinical and analytic variables, such as the International Prognostic Score developed for advanced cHL [10], but this still fails to identify a significant fraction of patients with very short failure-free survival [11]. In this context, the application of robust molecular techniques to identify molecular events and biological processes associated with treatment response is a necessary requisite for developing new predictive tools that enhance the www.aacrjournals.org. We have identified functional signatures associated with treatment response and showed the potential prognostic capacity of our assay finding a positive correlation between the expression of the proposed genes and treatment response
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