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Published on: September 20, 2016
The Dynamics of Nucleotide Variants in the Progression from Low-Intermediate Myeloma Precursor Conditions to Multiple
Bénedith Oben1,2, Charlotte Cosemans1,2,3, Ellen Geerdens4
1Laboratory Experimental Hematology, Department Clinical Biology, Jessa Hospital, 3500 Hasselt, Belgium.
Abstract:
Multiple myeloma (MM), or Kahler's disease, is an incurable plasma cell (PC) cancer in the bone marrow (BM). This malignancy is preceded by one or more asymptomatic precursor conditions, monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering multiple myeloma (SMM). The molecular mechanisms and exact cause of this progression are still not completely understood. In this study, the mutational profile underlying the progression from low-intermediate risk myeloma precursor conditions to MM was studied in serial BM smears. A custom capture-based sequencing platform was developed, including 81 myeloma-related genes. The clonal evolution of single nucleotide variants and short insertions and deletions was studied in serial BM smears from 21 progressed precursor patients with a median time of progression of six years. From the 21 patients, four patients had no variation in one of the 81 studied genes. Interestingly, in 16 of the 17 other patients, at least one variant present in MM was also detected in its precursor BM, even years before progression. Here, the variants were present in the pre-stage at a median of 62 months before progression to MM. Studying these paired BM samples contributes to the knowledge of the evolutionary genetic landscape and provides additional insight into the mutational behavior of mutant clones over time throughout progression.
Insights
Genetic mutations present in multiple myeloma (MM) are often detectable in precursor conditions years before diagnosis. This finding offers insights into the early molecular events driving MM progression.
Area of Science:
- Oncology
- Genetics
- Hematology
Background:
- Multiple myeloma (MM), also known as Kahler's disease, is an incurable cancer of plasma cells in the bone marrow.
- MM development is often preceded by asymptomatic conditions like monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM).
- The precise molecular mechanisms driving the progression from precursor conditions to MM remain largely unknown.
Purpose of the Study:
- To investigate the mutational profile associated with the progression from low-to-intermediate risk myeloma precursor conditions to MM.
- To analyze the clonal evolution of genetic variants in serial bone marrow samples from patients who progressed to MM.
Main Methods:
- Development of a custom capture-based sequencing platform targeting 81 myeloma-related genes.
- Analysis of serial bone marrow smears from 21 patients with progressed precursor conditions.
- Study of single nucleotide variants and short insertions/deletions to track clonal evolution over time.
Main Results:
- In 16 out of 17 patients, at least one genetic variant found in MM was also present in precursor bone marrow samples, often detected a median of 62 months before progression.
- Four patients showed no detectable variations within the 81 studied genes.
- The study provides insights into the genetic landscape and temporal behavior of mutant clones during MM progression.
Conclusions:
- Genetic alterations characteristic of multiple myeloma can be present in precursor stages years before clinical manifestation.
- Understanding these early genetic events is crucial for elucidating the progression pathways of MM.
- This research contributes to the knowledge of the evolutionary genetic landscape of multiple myeloma.
