{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T14:06:48Z","timestamp":1790777208416,"version":"4.1.0"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"8115","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nature"],"published-print":{"date-parts":[[2026,5,21]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    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\n                    <jats:sup>1<\/jats:sup>\n                    (more than 30,000\u00d7 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\u20132,854 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 (\n                    <jats:italic>PTEN<\/jats:italic>\n                    and\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    ), liver (\n                    <jats:italic>NF2L2<\/jats:italic>\n                    ) and spleen (\n                    <jats:italic>BRAF<\/jats:italic>\n                    and\n                    <jats:italic>NOTCH2<\/jats:italic>\n                    ), 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\n                    <jats:italic>TP53<\/jats:italic>\n                    , could be attributed to treatment. Immunotherapy, although not associated with increased mutagenesis, was linked to driver mutations in\n                    <jats:italic>PPM1D<\/jats:italic>\n                    and\n                    <jats:italic>TP53<\/jats:italic>\n                    , 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.\n                  <\/jats:p>","DOI":"10.1038\/s41586-025-09792-4","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T16:01:43Z","timestamp":1765382503000},"page":"900-910","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Somatic evolution following cancer treatment in normal 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D.M. reports speaker fees from AstraZeneca, Eli Lilly, BMS and Takeda, consultancy fees from AstraZeneca, Thermo Fisher, Takeda, Amgen, Janssen, MIM Software, Bristol Myers Squibb, Boehringer Ingelheim and Eli Lilly, and has received educational support from Takeda and Amgen. C.S. acknowledges grants from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc. collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical and Personalis. C.S. is chief investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee Chair; and co-chief investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAIL\u2019s SAB. C.S. receives consultant fees from Achilles Therapeutics (and is a SAB member), Bicycle Therapeutics (and is a SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre\u2013Shanghai, Metabomed (until July 2022), Relay Therapeutics (and is a SAB member), Saga Diagnostics (and is a SAB member) and the Sarah Cannon Research Institute. C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, Relay Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. C.S. declares a patent application for methods in lung cancer (PCT\/US2017\/028013); targeting neoantigens (PCT\/EP2016\/059401); identifying patent response to immune checkpoint blockade (PCT\/EP2016\/071471); methods for lung cancer detection (US20190106751A1); identifying patients who respond to cancer treatment (PCT\/GB2018\/051912); determining HLA LOH (PCT\/GB2018\/052004); predicting survival rates of patients with cancer (PCT\/GB2020\/050221), and methods and systems for tumour monitoring (PCT\/EP2022\/077987). C.S. is an inventor on a European patent application (PCT\/GB2017\/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity under their terms of employment C.S. is due a revenue share of any revenue generated from such license(s). M.J.-H. has received funding from CRUK, NIH National Cancer Institute, IASLC International Lung Cancer Foundation, Lung Cancer Research Foundation, Rosetrees Trust, UKI NETs and NIHR. M.J.-H. has consulted for Astex Pharmaceutical and Achilles Therapeutics, and is a member of the Achilles Therapeutics SAB and steering committee, has received speaker honoraria from Pfizer, Astex Pharmaceuticals, Oslo Cancer Cluster, Bristol Myers Squibb and Genentech. M.J.-H. is listed as a co-inventor on a European patent application relating to methods to detect lung cancer PCT\/US2017\/028013\u2014this patent has been licensed to commercial entities and, under terms of employment, M.J.-H. is due a share of any revenue generated from such license(s), and is also listed as a co-inventor on the GB priority patent application (GB2400424.4) with title: Treatment and Prevention of Lung Cancer. N.M. holds patents related to determining HLA LOH (PCT\/GB2018\/052004), determination of B cell fraction in mixed samples (PCT\/EP2024\/062999), determination of lymphocyte abundance in mixed samples (PCT\/EP2022\/070694), identifying responders to cancer treatment (PCT\/GB2018\/051912), targeting neoantigens (PCT\/EP2016\/059401), identifying patient response to immune checkpoint blockade (PCT\/EP2016\/071471), and predicting survival rates of patients with cancer (PCT\/GB2020\/050221), and has a patent pending in determining HLA disruption (PCT\/EP2023\/059039). The remaining authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}