Characterizing the mutational landscape of MM and its precursor MGUS

Area of Science:

• Cancer Genomics
• Myeloma Pathogenesis
• Biomarker Discovery

Background:

• Tumor mutational burden (TMB) and mutational signatures are prognostic biomarkers in cancer.
• The association between TMB and overall survival (OS) in newly diagnosed multiple myeloma (NDMM) is unclear.
• Mutational spectrum changes during the progression from MGUS to MM are unexplored.

Purpose of the Study:

• To investigate the mutational spectrum and TMB changes from MGUS to MM.
• To evaluate the association of TMB with OS in NDMM patients.
• To identify potential drivers of MGUS progression to MM.

Main Methods:

• Whole Exome Sequencing (WES) data from 1018 NDMM and 61 MGUS patients.
• Inference of single base substitutions, mutational signatures, and TMB.
• Analysis of variant frequencies, TMB values, and survival outcomes.

Main Results:

• A significant increase in non-synonymous, synonymous, and other variants from MGUS to MM.
• Increased TMB for non-synonymous and synonymous mutations in MM.
• Higher frequency of 3' and 5'UTR mutations in MM, potentially regulating progression.
• Hypermutators associated with poor OS and progression-free survival (PFS) in MM.
• Specific substitution patterns (increased C>A, C>T; decreased T>G) linked to poor outcomes.
• APOBEC activity significantly associated with poor OS in MM.

Conclusions:

• Mutational landscape significantly evolves from MGUS to MM.
• TMB and specific mutational signatures are associated with survival outcomes in NDMM.
• 3' and 5'UTR mutations may drive MGUS progression.
• APOBEC activity is a potential prognostic marker for poor survival in MM.
• Findings support risk-adapted therapies for MGUS and high-risk MM.