Application of Next-Generation Sequencing for the Genomic Characterization of Patients with Smoldering Myeloma
Department of Oncology and Hemato-oncology, University of Milan, 20122 Milan, Italy
Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy
Department of Clinical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
Hematology, “Azienda Ospedaliero-Universitaria di Parma”, 43126 Parma, Italy
Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
Author to whom correspondence should be addressed.
These authors are co-last authors.
Cancers 2020, 12(5), 1332; https://doi.org/10.3390/cancers12051332
Received: 16 March 2020 / Revised: 12 May 2020 / Accepted: 20 May 2020 / Published: 23 May 2020
(This article belongs to the Special Issue The Asymptomatic Version of Myeloma: MGUS and Smoldering Myeloma)
Genomic analysis could contribute to a better understanding of the biological determinants of the evolution of multiple myeloma (MM) precursor disease and an improved definition of high-risk patients. To assess the feasibility and value of next-generation sequencing approaches in an asymptomatic setting, we performed a targeted gene mutation analysis and a genome-wide assessment of copy number alterations (CNAs) by ultra-low-pass whole genome sequencing (ULP-WGS) in six patients with monoclonal gammopathy of undetermined significance and 25 patients with smoldering MM (SMM). Our comprehensive genomic characterization highlighted heterogeneous but substantial values of the tumor fraction, especially in SMM; a rather high degree of genomic complexity, in terms of both mutations and CNAs, and inter-patient variability; a higher incidence of gene mutations and CNAs in SMM, confirming ongoing evolution; intraclonal heterogeneity; and instances of convergent evolution. ULP-WGS of these patients proved effective in revealing the marked genome-wide level of their CNAs, most of which are not routinely investigated. Finally, the analysis of our small SMM cohort suggested that chr(8p) deletions, the DNA tumor fraction, and the number of alterations may have clinical relevance in the progression to overt MM. Although validation in larger series is mandatory, these findings highlight the promising impact of genomic approaches in the clinical management of SMM.