Somatic evolution following cancer treatment in normal tissue

Area of Science:

• Genomics
• Cancer Research
• Molecular Biology

Background:

• The contribution of external factors, like cancer therapies, to somatic evolution in healthy tissues is not fully understood.
• Somatic mutations accumulate in normal cells throughout life due to various exposures.

Purpose of the Study:

• To investigate the impact of exogenous sources, including cancer treatments, on somatic mutation acquisition and selection in normal human tissues.
• To characterize mutational signatures and identify driver mutations in normal tissues across different organs.

Main Methods:

• Analysis of 168 cancer-free tissue samples from 22 patients using high-depth duplex sequencing (>30,000× coverage).
• Identification and characterization of somatic mutations, mutational signatures, and selection processes.
• Correlation of mutation acquisition with patient therapies and lifestyle factors (alcohol, smoking).

Main Results:

• Somatic mutations were detected in all analyzed samples, with significant contributions from exogenous sources like alcohol, smoking, and cancer therapies.
• Exogenous sources accounted for over 40% of mutations in liver tissue but less than 10% in brain tissue.
• Cancer treatments, particularly systemic therapies, were linked to over 25% of driver mutations in normal tissues, including TP53.
• Immunotherapy, while not increasing mutagenesis, was associated with driver mutations in PPM1D and TP53.

Conclusions:

• Exogenous exposures, including cancer treatments, profoundly influence somatic evolution in normal tissues.
• Tissue-specific selection processes shape the landscape of mutations and driver events.
• Understanding these processes is crucial for comprehending normal tissue biology and the long-term effects of therapies.