Diffuse large B-cell lymphoma - tumour characteristics on RNA and protein level associated with prognosis

Abstract: Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoma subtype. In Sweden 450 new cases are diagnosed annually. With modern anthracycline-containing chemotherapy DLBCL is potentially curable, with an estimated overall cure rate of approximately 50% for patients with advanced stage disease. Through molecular profiling of DLBCL the ?cell-of-origin concept? has been established: patients with tumours expressing genes characteristic of germinal center B-cells, ?GC-profile? has a significantly better survival than patients with tumors expressing genes normally induced during in vitro activation of peripheral blood B-cells, ?ABC-profile?. The first study (n=125) aimed to identify a protein pattern that could be used for discriminating germinal center derived (GC) and activated B-cell like (ABC)/non-GC DLBCL, using immunohistochemistry (IHC). BCL6, CD10 and CD40 were chosen as markers of a GC-phenotype, CD23 as a marker of pre/early GC-origin and CD138 as a marker of post-GC origin (i.e non-GC). No prognostically different subgroups, corresponding to GC or ABC (non-GC) could be identified. A new finding was the positive prognostic impact of CD23 and CD40 expression. In the second study (n=125) the prognostic effect of CD40, but not CD23, was confirmed. The effect of CD40 effect could not be explained by association with the GC-phenotype or by an enhanced autologous tumour response, as detected by tumour infiltrating helper and cytotoxic T-lymphocytes. The prognostic effect of a GC versus non-GC phenotype according to Hans et al (Blood 2004) was confirmed. The third study (n=122) identified the tissue microarray technique to be unreliable for immunohistochemical detection in GC vs. non-GC phenotypes, mostly due to difficulties interpreting BCL6 status. In the fourth study tumours from patients with cured (n=24) versus primary chemotherapy-refractory DLBCL (n=13), were investigated with respect to gene expression profiles, using spotted 55K oligonucleotide arrays produced in Lund. The genes that most differed between chemotherapy sensitive and refractory tumours mainly coded for proteins expressed by cells in the tumour microenvironment, and not by the tumour cells themselves. Confirmative IHC showed that the frequency of tumour infiltrating lymphocytes, macrophages and reactive cells expressing proteolytic and pro-inflammatory proteins were higher in the chemo-sensitive cohort, indicating that the microenvironment has an impact on the response to chemotherapy in DLBCL.