From Germline Susceptibility to Therapeutic Vulnerability: DNA Damage Response Gene Mutations Driving Multiple...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Multiple myeloma (MM) exhibits genomic instability and resistance to therapies.
• Germline DNA damage response (DDR) mutations (e.g., BRCA1/2, ATM, CHEK2) are linked to MM susceptibility and progression.
• Inherited DDR defects influence chromosomal instability and the tumor immune microenvironment.

Purpose of the Study:

• To review the mechanistic and clinical significance of germline DDR alterations in MM.
• To highlight the translational potential of DDR alterations in precision oncology.

Main Methods:

• Review of recent advances in multiomics profiling.
• Analysis of single-cell sequencing data.
• Evaluation of liquid biopsy techniques for monitoring DDR alterations.

Main Results:

• Germline DDR mutations contribute to MM clonal evolution and therapeutic resistance.
• DDR defects can facilitate disease progression under therapy pressure.
• Advances in multiomics and sequencing enhance the interpretation and monitoring of DDR alterations.

Conclusions:

• Germline DDR alterations are crucial in MM pathogenesis and progression.
• Targeting DDR vulnerabilities presents opportunities for novel precision therapies, such as PARP inhibitors.
• Further research into germline DDR defects can advance personalized treatment strategies for MM.