Caracterización molecular de la macroglobulinemia de waldenströmimplicaciones en el diagnóstico, pronóstico y transformación histológica

Resum

Waldenström’s macroglobulinemia (WM) is a rare indolent B-cell lymphoproliferative disorder that presents wide heterogeneity at the clinical level. The behavior of this disease ranges from indolent (IgM monoclonal gammopathy of undetermined significance, IgM-MGUS, and asymptomatic WM) to highly symptomatic forms. Causes underlying this clinical heterogeneity, as well as the physiopathological mechanisms leading the disease progression remain to be clarified. In this work, we have observed that the recently identified MYD88 L265P somatic mutation is a highly characteristic marker of the disease, but is present equally in WM and IgM-MGUS (86% and 87% of patients, respectively), therefore not being responsible for the clinical heterogeneity. In contrast, we have found that the frequency of other genetic alterations progressively increased from IgM-MGUS to asymptomatic WM and symptomatic WM, meaning that, unlike MYD88 L265P, present from the beginning of the pathogenesis, most of these mutations would be acquired as the disease evolves. In addition to the higher number of mutations, data from gene expression profiling revealed significant differences between indolent and symptomatic patients, regarding genes involved in WM pathogenic mechanisms (TLR/MYD88, CXCR4 and BCR pathways). This profile provided some clues about the heterogeneity of this disease and had an impact on the clinics. Finally, we focused on WM transformation to diffuse large B-cell lymphoma (DLBCL), an event that occurs in up to 10% of patients and is associated with an adverse outcome. We performed a whole-exome sequencing study comparing tumor DNA of patients at diagnosis (WM) and transformation to DLBCL. Analysis showed extensive genetic heterogeneity with a large number of alterations, reflecting the complexity associated with the transformation process. Although we could not identify a unique genetic event, certain genes were frequently mutated at diagnosis in patients who suffered an histological transformation (i.e. CD79B), suggesting their potential role as biomarkers for predicting the risk of transformation.