Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma.

Area of Science:

• Genomics
• Cancer Biology
• Hematology

Background:

• Understanding the temporal sequence of genetic events in multiple myeloma (MM) is crucial for deciphering its pathogenesis.
• The acquisition timing of chromosomal abnormalities and their impact on clinical outcomes remain incompletely understood.

Purpose of the Study:

• To investigate the temporal relationship between initiating and driver genetic events in MM.
• To determine the impact of the timing of chromosomal alterations on MM patient prognosis.

Main Methods:

• Analysis of 421 whole-genome sequencing profiles from 382 MM patients.
• Utilizing clock-like mutational signatures to estimate time lags between genetic events and diagnosis.
• Investigating the order of acquisition for chromosomal abnormalities like hyperdiploidy and 1q gain.

Main Results:

• A significant time lag of 2-4 decades was estimated between initiating MM events and clinical diagnosis.
• Trisomies in hyperdiploid MM can be acquired concurrently with other gains, such as 1q gain.
• Hyperdiploidy acquisition was found to occur after IGH translocation when both events are present.
• Early 1q gain was associated with adverse outcomes, comparable to 1q amplification, and worse than late 1q gain.

Conclusions:

• The timing of 1q gain/amplification acquisition is a critical determinant of prognostic impact in MM, potentially more so than the copy number.
• This study enhances the understanding of MM's evolutionary history and offers potential prognostic insights.