Somatic evolution following cancer treatment in normal tissue

Pich, O; Ward, S; Rowan, A; Naceur-Lombardelli, C; Shutkever, O; Martinez-Ruiz, C; Harries, S; Hessey, S; Naidu, B; Brenton, JD; Le Quesne, J; Thomas, A; Richards, C; Krebs, MG; Turajlic, S; Jogai, S; Zaccaria, S; Moore, D; Hiley, CT; PEACE Consortium; Swanton, C; Jamal-Hanjani, M; McGranahan, N

Author(s): Pich, O; Ward, S; Rowan, A; Naceur-Lombardelli, C; Shutkever, O; Martinez-Ruiz, C; Harries, S; Hessey, S; Naidu, B; Brenton, JD; Le Quesne, J; Thomas, A; Richards, C; Krebs, MG; Turajlic, S; Jogai, S; Zaccaria, S; Moore, D; Hiley, CT; PEACE Consortium; Swanton, C; Jamal-Hanjani, M; McGranahan, N;
Details: Publication Year 2026-05,Volume 653,Issue #8115,Page 900-910
Journal Title: Nature
Publication Type: Research article
Abstract: The extent to which exogenous sources, including cancer treatment, contribute to somatic evolution in normal tissue remains unclear. Here we used high-depth duplex sequencing(1) (more than 30,000× coverage) to analyse 168 cancer-free samples representing 16 organs from 22 patients with metastatic cancer enroled in the PEACE research autopsy study. In every sample, we identified somatic mutations (range 305-2,854 mutations) at low variant allele frequencies (median 0.0000323). We extracted 16 distinct single-base substitution mutational signatures, reflecting processes that have moulded the genomes of normal cells. We identified alcohol-induced mutation acquisition in liver, smoking-induced mutagenesis in lung and cardiac tissue, and multiple treatment-induced processes, which correlated with therapy type and duration. Exogenous sources, including treatment, underpinned, on average, more than 40% of mutations in liver but less than 10% of mutations in brain samples. Finally, we observed tissue-specific selection, with positive selection in tissues such as lung (PTEN and PIK3CA), liver (NF2L2) and spleen (BRAF and NOTCH2), and limited selection in others, such as brain and cardiac tissue. More than 25% of driver mutations in normal tissue exposed to systemic anti-cancer therapy, including in TP53, could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in PPM1D and TP53, illustrating how non-mutagenic treatment can sculpt somatic evolution. Our study reveals the rich tapestry of mutational processes and driver mutations in normal tissue, and the profound effect of lifetime exposures, including cancer treatment, on somatic evolution.
Publisher: Springer Nature
Keywords: Female; Humans; Male; Brain/metabolism/drug effects; *Clonal Evolution/genetics/drug effects; Ethanol/adverse effects; *Evolution, Molecular; Gene Frequency; Liver/drug effects/metabolism/pathology; Lung/drug effects/metabolism/pathology; Mutagenesis/drug effects/genetics; *Mutation/drug effects; Myocardium/metabolism; *Neoplasms/genetics/pathology/therapy/drug therapy; Organ Specificity/genetics/drug effects; Selection, Genetic/drug effects; Smoking/adverse effects; PTEN Phosphohydrolase; Class I Phosphatidylinositol 3-Kinases
Department(s): Laboratory Research
Publisher's Version: https://doi.org/10.1038/s41586-025-09792-4
Open Access at Publisher's Site: https://doi.org/10.1038/s41586-025-09792-4
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-06-16 02:11:46

Last Modified: 2026-06-16 02:11:53