Context-dependent selection sculpts mutational landscapes in the normal lung.

Area of Science:

• Genetics
• Evolutionary Biology
• Oncology

Background:

• Organismal evolution responds to environmental shifts.
• Somatic evolution in tissues is influenced by aging, lifestyle, and exposures.
• Understanding somatic mutations in normal tissues is crucial for disease prevention.

Purpose of the Study:

• To investigate somatic evolution in non-malignant lung tissue.
• To identify how aging, smoking, and therapies affect mutation selection.
• To compare mutation selection in normal lung tissue versus lung cancer.

Main Methods:

• Deep mutational profiling using duplex sequencing.
• Analysis of over 370 non-malignant lung tissue samples from 202 subjects.
• Multiregional profiling of mutational landscapes.

Main Results:

• Aging, smoking, and anti-cancer therapies are associated with specific mutation selection in normal lung tissue.
• Mutations in cancer driver genes show distinct selection patterns in normal tissue compared to lung cancers.
• An expanded spectrum of sites under selection was observed in normal lung tissue.
• Convergent evolution was identified within individual lungs through multiregional profiling.

Conclusions:

• Somatic evolution in normal lung tissue is driven by aging and lifetime exposures.
• The selection of mutations in normal tissue differs significantly from that in lung cancers.
• Insights into clonal selection forces are critical for managing diseases associated with aging and exposures.