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Multidimensional Coculture System to Model Lung Squamous Carcinoma Progression

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Published on: March 17, 2020

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

Edward Evans¹, Ferriol Calvet², Fabio Marongiu^1,3

¹Departments of Biochemistry and Molecular Genetics, Immunology and Microbiology, and Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.

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|July 10, 2026

Summary

Somatic evolution in normal lung tissue is shaped by aging and exposures, influencing mutations differently than in cancer. Understanding these forces is key to managing age-related diseases.

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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.