Timing the initiation of multiple myeloma

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• The evolutionary timeline and mutational landscape of multiple myeloma (MM) and its precursor conditions remain incompletely understood.
• Investigating these processes is crucial for developing effective prevention and early detection strategies.

Purpose of the Study:

• To elucidate the landscape and timing of mutational processes driving the evolution of multiple myeloma.
• To identify specific mutational signatures and their chronological activity throughout MM development.

Main Methods:

• Analysis of whole-genome (n=89) and exome (n=973) sequencing data from a large cohort of multiple myeloma patients.
• Reconstruction of the chronological activity of identified mutational signatures.

Main Results:

• Identification of eight distinct mutational processes, including a signature linked to melphalan exposure.
• Estimation that the initial transformation of germinal center B-cells typically occurs between the second and third decades of life.
• Definition of four patterns of activation-induced deaminase (AID) and apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) mutagenesis, with some patients showing prolonged AID activity in the pre-malignant phase.

Conclusions:

• The study provides a chronological framework for understanding multiple myeloma evolution.
• Findings highlight the role of specific mutational processes and suggest potential targets for intervention.
• Insights into prolonged AID activity point towards antigen-responsiveness and germinal center dynamics in MM pathogenesis.