A search for prognostic biomarkers in diffuse large B-cell lymphoma with proteomics and immunohistochemistry

Abstract

Diffuse large B-cell lymphoma (DLBCL), the most common lymphoma in the Western world, can by gene expression profiling or immunohisto-chemistry (IHC), be divided into two subgroups according to its “cell-of-origin”. The subgroup ABC (or non-GCB) with similarities to active post-germinal centre B-cells, is associated with worse outcome. In addition, patients with primary refractory disease or early relapse have a very dismal prognosis. The aim of this thesis has been to identify novel prognostic biomarkers in a large retrospective DLBCL patient cohort by mass-spectrometry (MS)-based proteomics and IHC. Quantitative MS-based proteomics (QMS) revealed several differentially expressed proteins between refractory/relapsed patients (REF/REL) and patients with progression-free survival ≥5 years (CURED). Many ribosomal proteins were up-regulated in REF/REL patients while numerous proteins associated with the actin cytoskeleton were up-regulated in CURED patients. By using QMS we also found several up-regulated proteins in non-GCB DLBCL related to the tumour microenvironment, including interferon (IFN)-stimulated proteins. By using IHC we found a prognostic association for two proteins (CREBBP and TBLR1) that are frequently mutated in DLBCL, and for IFI16 and MNDA, both belonging to the pyrin and hematopoietic IFN-inducible nuclear (PYHIN) family. In conclusion, we have found increased expression of several proteins or groups of proteins not previously described in DLBCL and with potential prognostic impact. Further functional studies are warranted to elucidate their role in immunochemotherapy resistance.