Chemotherapy and the somatic mutation burden of sperm

Area of Science:

• Genetics
• Oncology
• Reproductive Health

Background:

• Chemotherapy agents are known to induce DNA damage for cancer treatment.
• The effects of chemotherapy on mutagenesis in normal cells, particularly sperm, remain largely uncharacterized.

Purpose of the Study:

• To investigate the impact of diverse chemotherapies on mutation burden in normal human tissues, including sperm.
• To assess the potential long-term genetic consequences of cancer therapies on individuals and their offspring.

Main Methods:

• Application of high-fidelity duplex sequencing to analyze mutation burdens in 94 samples from 36 chemotherapy-exposed individuals and 32 controls.
• Validation of findings across multiple tissues (sperm, saliva, blood, liver) in humans and in a mouse model treated with cisplatin.

Main Results:

• Elevated mutation burden observed in sperm samples from chemotherapy-exposed men compared to controls, with some individuals showing a >10-fold increase.
• Increased mutation burden was also detected in saliva, blood, and liver tissues of chemotherapy-exposed subjects.
• Cisplatin treatment in mice led to increased mutation burdens in sperm, liver, and hematopoietic progenitor cells.

Conclusions:

• Chemotherapy is associated with a significant increase in DNA mutation burden across various normal tissues.
• These findings highlight potential risks for cancer patients undergoing chemotherapy, particularly concerning reproductive health and genetic counseling.
• The study underscores the importance of considering mutation accumulation when counseling patients about sperm banking and future reproductive choices.