Extensive and differential platinum chemotherapy mutagenesis in livers of children

• 成果类型: Article
• 署名作者: Wenger, Anna; Vannier, Jean-Baptiste; Lee-Six, Henry; Loesch, Robin; Emanuelli, Giulia; Dave, Manas; Layeghifard, Mehdi; Lawson, Andrew R. J.; Abascal, Federico; Nicola, Pantelis A.; Treger, Taryn D.; Ogbonnah, Toochi; Parks, Conor; Oliver, Thomas R. W.; Kennedy, Jonathan; Hodder, Angus; Anderson, Nathaniel D.; Torres Silva, Felipe Luz; Trinh, Mi K.; Dowe, Thomas; Habarwaa, Marwo; Sun, James J.; Assia-Zamora, Sergio; Cortes-Cerisuelo, Miriam; Jassem, Wayel; Town, Charlotte; Dhawan, Anil; Jain, Vandana; Straathof, Karin; Deheragoda, Maesha; Martincorena, Inigo; Palm, Liina; Hutchinson, J. Ciaran; Coorens, Tim H. H.; Trayers, Claire; Yuneva, Mariia; Heaton, Nigel; Shlien, Adam; Zen, Yoh; Rouhani, Foad J.; Behjati, Sam
• 署名单位: Wellcome Trust Sanger Institute; University of Gothenburg; Francis Crick Institute; University of Cambridge; Francis Crick Institute; University of Toronto; Hospital for Sick Children (SickKids); University of Cambridge; University of London; University College London; Great Ormond Street Hospital for Children NHS Foundation Trust; University of London; University College London; Universidade Federal de Amazonas; King's College Hospital NHS Foundation Trust; University of London; King's College London; University College London; King's College Hospital NHS Foundation Trust; King's College Hospital; King's College Hospital NHS Foundation Trust; King's College Hospital; King's College Hospital NHS Foundation Trust; King's College Hospital; European Molecular Biology Laboratory (EMBL); European Bioinformatics Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of Toronto
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.ady0339
• 发表日期: 2026-09-10
• 页码: eady0339
• 关键词: CHILDHOOD-CANCER; mutational signatures; clonal hematopoiesis; genome; cisplatin; genes; insertions; landscape; neoplasms; deletions

摘要

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.