RAS/RAF landscape in monoclonal plasma cell conditions
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Published on: December 22, 2015
Anais Schavgoulidze1, Jill Corre1, Mehmet Kemal Samur2
1Myeloma Genomic Lab, Institut Universitaire du Cancer Toulouse-Oncopole, Toulouse, France.
Abstract:
Multiple myeloma is characterized by a huge heterogeneity at the molecular level. The RAS/RAF pathway is the most frequently mutated, in ∼50% of the patients. However, these mutations are frequently subclonal, suggesting a secondary event. Because these genes are part of our routine next-generation sequencing panel, we analyzed >10 000 patients with different plasma cell disorders to describe the RAS/RAF landscape. In this large cohort of patients, almost 61% of the patients presented a RAS/RAF mutation at diagnosis or relapse, but much lower frequencies occurred in presymptomatic cases. Of note, the mutations were different from that observed in solid tumors (higher proportions of Q61 mutations). In 29 patients with 2 different mutations, we were able to perform single-cell sequencing, showing that in most cases, mutations occurred in different subclones, suggesting an ongoing mutational process. These findings suggest that the RAS/RAF pathway is not an attractive target, both on therapeutic and residual disease assessment points of view.
Insights
RAS/RAF pathway mutations are common in multiple myeloma, but often occur as secondary events in different subclones. This suggests the RAS/RAF pathway may not be an ideal therapeutic target in plasma cell disorders.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Multiple myeloma exhibits significant molecular heterogeneity.
- The RAS/RAF pathway is frequently mutated in plasma cell disorders, often as a subclonal event.
Purpose of the Study:
- To characterize the RAS/RAF mutation landscape in a large cohort of plasma cell disorder patients.
- To investigate the clonal architecture of RAS/RAF mutations using single-cell sequencing.
Main Methods:
- Analysis of next-generation sequencing data from over 10,000 patients with plasma cell disorders.
- Single-cell sequencing on 29 patients with multiple RAS/RAF mutations.
Main Results:
- Approximately 61% of patients presented with RAS/RAF mutations at diagnosis or relapse.
- RAS/RAF mutation frequencies were lower in presymptomatic cases.
- Mutations differed from those in solid tumors, with a higher proportion of Q61 mutations.
- Single-cell sequencing revealed mutations often occurred in distinct subclones, indicating ongoing mutational processes.
Conclusions:
- RAS/RAF pathway mutations are prevalent but often secondary in plasma cell disorders.
- The subclonal nature of these mutations suggests they may not be suitable targets for therapy or residual disease monitoring.
