Extensive and differential platinum chemotherapy mutagenesis in livers of children
Childhood cancer survivors often experience late adverse effects that may be linked to chemotherapy mutagenesis. We studied chemotherapy mutagenesis in normal pediatric tissues using duplex sequencing (NanoSeq) to enable the detection of mutations from single DNA molecules. We found that platinum chemotherapeutics increased the mutation burdens of normal pediatric tissues to levels seen in adults. In the liver, platinum agents imparted a tissue-specific mutational signature that was absent from other tissues. Gene-focused duplex sequencing revealed that chemotherapy mutagenesis generates a great diversity of nonsynonymous variants, some of which may have functional potential, such as leukemogenic variants in blood. Our findings demonstrate extensive chemotherapy mutagenesis in normal tissues of children, which may provide a plausible link between chemotherapy exposure and adverse effects in later life.
Authors
- Felipe Luz Torres Silva (ORCID: https://orcid.org/0000-0003-4292-0027)
- James J. Sun (ORCID: https://orcid.org/0000-0002-1477-5769)
- Robin Loesch
- Mi K. Trinh (ORCID: https://orcid.org/0000-0003-4185-0071)
- Liina Palm
- Angus Hodder (ORCID: https://orcid.org/0009-0003-2577-0677)
- Iñigo Martincorena (ORCID: https://orcid.org/0000-0003-1122-4416)
- Karin Straathof (ORCID: https://orcid.org/0000-0001-9673-8568)
- Federico Abascal (ORCID: https://orcid.org/0000-0002-6201-1587)
- Anil Dhawan (ORCID: https://orcid.org/0000-0002-4942-0845)
- Wayel Jassem (ORCID: https://orcid.org/0000-0003-2918-5232)
- Claire Trayers (ORCID: https://orcid.org/0000-0003-0236-6041)
- Henry Lee-Six (ORCID: https://orcid.org/0000-0003-4831-8088)
- Giulia Emanuelli (ORCID: https://orcid.org/0000-0001-8899-6110)
- J. Ciaran Hutchinson (ORCID: https://orcid.org/0000-0002-1708-2634)
- Foad J. Rouhani (ORCID: https://orcid.org/0000-0002-2334-1305)
- Manàs Dave (ORCID: https://orcid.org/0000-0002-1676-801X)
- Thomas R. W. Oliver (ORCID: https://orcid.org/0000-0003-4306-0102)
- Tim Coorens (ORCID: https://orcid.org/0000-0002-5826-3554)
- Adam Shlien (ORCID: https://orcid.org/0000-0002-0368-5370)
- Anna Wenger (ORCID: https://orcid.org/0000-0001-6063-5401)
- Sam Behjati (ORCID: https://orcid.org/0000-0002-6600-7665)
- Andrew Lawson (ORCID: https://orcid.org/0000-0003-3592-1005)
- Taryn D. Treger (ORCID: https://orcid.org/0000-0002-7204-4737)
- Yoh Zen (ORCID: https://orcid.org/0000-0001-8370-6508)
- Nathaniel D. Anderson (ORCID: https://orcid.org/0000-0003-4523-6327)
- Pantelis Nicola (ORCID: https://orcid.org/0000-0002-8641-3580)
- Sergio Assia‐Zamora (ORCID: https://orcid.org/0000-0002-0927-3828)
- Jean‐Baptiste Vannier (ORCID: https://orcid.org/0000-0002-4471-1854)
- Mehdi Layeghifard (ORCID: https://orcid.org/0000-0002-6224-3628)
- Conor Parks (ORCID: https://orcid.org/0000-0003-0240-0684)
- Marwo Habarwaa
- Jonathan Kennedy (ORCID: https://orcid.org/0009-0002-4953-4639)
- Thomas Dowe
- Miriam Cortes-Cerisuelo
- Maesha Deheragoda
- Mariia Yuneva
- Toochi Ogbonnah
- Charlotte Town (ORCID: https://orcid.org/0009-0004-5588-0655)
- Vandana Jain
- Nigel Heaton
Institutions
- Broad Institute (US)
- European Bioinformatics Institute (GB)
- University of Toronto (CA)
- University of Cambridge (GB)
- Great Ormond Street Hospital (GB)
- The Francis Crick Institute (GB)
- Hospital for Sick Children (CA)
- Cambridge University Hospitals NHS Foundation Trust (GB)
- Wellcome Sanger Institute (GB)
- Foundation for Liver Research (GB)
- King's College Hospital NHS Foundation Trust (GB)
- Kings Health Partners (GB)
- King's College Hospital (GB)
- University College London (GB)
- Universidade Federal do Amazonas (BR)
- University of Gothenburg (SE)
Publication Details
- Journal
- Science
- Published
- 2026-09-10
- DOI
- https://doi.org/10.1126/science.ady0339
- Citations
- 1
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 3.53