RAS/RAF landscape in monoclonal plasma cell conditions.

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.