Abstract
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.
Highlights
The recent progress in next-generation sequencing (NGS) techniques applied to multiple myeloma (MM) has prompted comprehensive characterizations of genomic alterations in malignant plasma cells (PCs) through clinical-grade approaches [1,2]
Our targeted panel identified a median of one mutation per patient in monoclonal gammopathy of undetermined significance (MGUS) and two in smoldering MM (SMM), without a statistically significant difference between the distributions of the two groups (Figure 1a)
The detection of somatic gene mutations in bone marrow (BM) CD138+ cells could be undermined by the presence of normal PCs in the sample
Summary
The recent progress in next-generation sequencing (NGS) techniques applied to multiple myeloma (MM) has prompted comprehensive characterizations of genomic alterations in malignant plasma cells (PCs) through clinical-grade approaches [1,2]. Different types of genomic lesions may contribute to myelomagenesis and have a prognostic impact. Their detection, currently requires the use of multiple molecular techniques (fluorescence in situ hybridization (FISH), Sanger sequencing, and single nucleotide polymorphism arrays), which makes analysis expensive and technically demanding. A large number of PCs is required. This may represent a limitation, especially in the pre-malignant stages of the disease, i.e., monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM). A poor recovery of clonal CD138+ cells from the bone marrow (BM)
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