Genomic landscape of IgM-MGUS and patients with stable or progressive asymptomatic Waldenström macroglobulinemia
Abstract
Abstract Immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (IgM-MGUS) and asymptomatic Waldenström macroglobulinemia (WM; aWM) are precursor conditions of symptomatic WM with an annual 1.5% to 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 229 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 with the stable aWM (aWMst) group, whereas MYD88L265 variant allele frequency was significantly higher in patients with aWMpr than those with aWMst. In addition, patients with IgM-MGUS with MYD88WT genotype showed a distinct genomic profile compared with 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.
Article Details
Authors (23)
Tina Bagratuni
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Ourania Theologi
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Christos Vlachos
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Ioannis Kollias
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Kylee Maclachlan
2Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
Foteini Aktypi
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Nefeli Mavrianou-Koutsoukou
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Christine Liacos
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Konstantina Taouxi
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Alexandra Papadimou
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Katerina Chrisostomidou
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Maria Sakkou
1Department of Clinical Therapeutics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Irene Solia
12Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Athens, Greece
Foteini Theodorakakou
Department of Clinical Therapeutics, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece
Gianmarco Favrin
University of Pavia, Pavia, Italy
Maria Gavriatopoulou
National and Kapodistrian University of Athens
Evangelos Terpos
Marzia Varettoni
4Division of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Policlinico San Matteo, Pavia, Italy
Zachary R. Hunter
Steven Treon
5Bing Center for Waldenström’s Macroglobulinemia, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
Francesco Maura
Memorial Sloan Kettering Cancer Center, New York
Meletios A. Dimopoulos
Efstathios Kastritis