Genomic landscape of IgM-MGUS and patients with stable or progressive asymptomatic Waldenström macroglobulinemia.

IgM-Monoclonal gammopathy of undetermined significance (IgM-MGUS) and asymptomatic Waldenström (aWM) are precursor conditions of symptomatic Waldenström macroglobulinemia (sWM) with an annual 1.5-12% risk of progression. Although clinical prognostic models exist for risk stratification, it remains challenging to distinguish asymptomatic patients who will eventually progress from those who will not. Hence, the characterization of genomic features that shape disease progressors could potentially improve risk stratification. We performed whole-exome sequencing on 232 samples from 139 patients, including 9 patients with sequential samples. We observed an increasing mutation burden through the stages of disease evolution. Genes such as CD79B, ARID1A and CREBBP were more often mutated in the aWM progressed (aWMpr) compared to the non-progressor aWM group (aWMst) while MYD88L265 variant allele frequency (VAF) was significantly higher in aWMpr compared to aWMst patients. In addition, IgM-MGUS patients with MYD88WT genotype showed a distinct genomic profile compared to the MYD88MUT patients. Furthermore, the presence of more aneuploidies showed a significant association with a higher risk of progression to the symptomatic disease. Overall, our study shows that genomic profiling of patients' tumor at the time of aWM diagnosis might represent an improved strategy for identifying patients at high risk to progression who could benefit from earlier intervention.