Classic Hodgkin Lymphoma Refractory for ABVD Treatment Is Characterized by Pathologically Activated Signal Transduction Pathways as Revealed by Proteomic Profiling

SIMPLE SUMMARY: Classic Hodgkin lymphoma (cHL) patients refractory to standard ABVD chemo-therapy are known to have a dismal prognosis. This has led to the hypothesis that ABVD treatment-sensitive and ABVD treatment-refractory tumours are biologically distinct. In this study, cHL patients refractory to standard ABVD treatment show subtle but significant differences in protein expression that enable clustering of the two response groups, thus indicating differences between ABVD sensitive and refractory patients at the molecular level, and thereby strengthening the hypothesis that ABVD sensitive and ABVD refractory tumours may be biologically distinct. ABSTRACT: In classic Hodgkin lymphoma (cHL), the tumour microenvironment (TME) is of major pathological relevance. The paucity of neoplastic cells makes it important to study the entire TME when searching for prognostic biomarkers. Cure rates in cHL have improved markedly over the last several decades, but patients with primary refractory disease still show inferior survival. We performed a proteomic comparison of pretreatment tumour tissue from ABVD treatment-refractory versus ABVD treatment-sensitive cHL patients, in order to identify biological differences correlating with treatment outcome. Formalin-fixed paraffin-embedded tumour tissues from 36 patients with cHL, 15 with treatment-refractory disease, and 21 with treatment-sensitive disease, were processed for proteomic investigation. Label-free quantification nano liquid chromatography tandem mass spectrometry was performed on the tissues. A total of 3920 proteins were detected and quantified between the refractory and sensitive groups. This comparison revealed several subtle but significant differences in protein expression which could identify subcluster characteristics of the refractory group. Bioinformatic analysis of the biological differences indicated that a number of pathologically activated signal transduction pathways are disturbed in ABVD treatment-refractory cHL.