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The work presents four clinical cases and uses whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples to trace distinct developmental routes. Cytotoxic therapies link to secondary acute myeloid leukemia, while early embryonic somatic drivers and independent embryogenesis explain other cases. Platinum exposure yields at least order-of-magnitude more mutations per day than aging in normal tissues.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/origins-of-second-malignancies-in-children-and-mutational-footprint-of-chemotherapy-in-normal-tissues-research-brief/330770/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/origins-of-second-malignancies-in-children-and-mutational-footprint-of-chemotherapy-in-normal-tissues-research-brief/330770.png","ImageObject",300,407,{"name":92,"@type":93},"Hazel","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-04","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":29},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why are second malignancies in children considered extremely rare in this study?","Question",{"text":112,"@type":113},"Children without known germline predisposing conditions developing a second malignancy during developmental ages are described as extremely uncommon.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How did the researchers determine the origins of the second cancers?",{"text":117,"@type":113},"They analyzed tumor and normal samples using whole-genome sequencing and error-correcting ultra-deep duplex sequencing to uncover different development routes.",{"name":119,"@type":110,"acceptedAnswer":120},"What role did platinum-based chemotherapy play in mutation accumulation?",{"text":121,"@type":113},"Platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},330770,1790240782,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":29,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":41,"preview_page_count":4},137441390410,"https://ap-avatar.wpscdn.com/avatar/2000252f4ab5702993?_k=1776741390130283984","Mònica Sánchez-Guixé1,2, Ferran Muiños1,2, Morena Pinheiro-Santin1, Víctor González-Huici1, Carlos J. Rodriguez-Hernandez3, Alexandra Avgustinova1,3, Cinzia Lavarino4, Abel González-Pérez1,2,5, Jaume Mora4, and Núria López-Bigas1,2,5,6  \nRESEARCH BRIEF  \nOrigins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues  \nABSTRACT  Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are  \nextremely rare. We present four such clinical cases and, through whole-genome and error-correcting ultra-deep duplex sequencing of tumor and normal samples, we explored the origin of the second malignancy in four children, uncovering different routes of development. The exposure to cytotoxic therapies was linked to the emergence of a secondary acute myeloid leukemia. A common somatic mutation acquired early during embryonic development was the driver of two solid malignancies in another child. In two cases, the two tumors developed from completely independent clones diverging during embryogenesis. Importantly, we demonstrate that platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.  \nSIGNIFICANCE: Using whole-genome and error-correcting ultra-deep duplex sequencing, we uncover different origins for second neoplasms in four children. We also uncover the presence of platinumrelated mutations across 10 normal tissues of exposed individuals, highlighting the impact that the use of cytotoxic therapies may have on cancer survivors.  \nSee related commentary by Pacyna and Nangalia, p. 900.  \nINTRODUCTION  \nChildhood cancers are all rare diseases, most with some evidence of an embryonal cell of origin (1) . In extremely unusual instances, a second tumor presents years after a child is cured of a first primary malignancy. If this second tumor is of a different type and unrelated to the first malignancy,  \n1 Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain. 2Centro de Investigación Biomédica en Red en Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid, Spain. 3 Institut de Recerca Sant Joan de Déu, Barcelona, Spain.  \n4Pediatric Cancer Center Barcelona (PCCB), Hospital Sant Joan de Déu, Barcelona, Spain. 5Universitat Pompeu Fabra, Barcelona, Spain. 6 Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.  \nA. González-Pérez and N. López-Bigas contributed equally to this article. Corresponding Authors: Nuria Lopez-Bigas, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and  \nthere are several possibilities to explain its origin. It may be related to underlying germline cancer predisposition (e.g., anosteosarcoma developing in an RB mutated individual having survived a retinoblastoma previously; ref. 2) or an early mosaic somatic mutation acquired during fetal development (3) . Exceptionally, two tumors of the same type have been  \nTechnology, Baldiri Reixac, 10, 08028 Barcelona, Spain. E-mail: nuria.lopez@ [irbbarcelona.org](irbbarcelona.org); Jaume Mora, SJD Pediatric Cancer Center Barcelona, Santa Rosa, 39-57, 4th Floor, PCCB, 08950 Esplugues de Llobregat, Spain. E-mail: [jaume.mora@sjd.es](jaume.mora@sjd.es)  \nCancer Discov 2024;14:953–64  \ndoi: 10. 1158/2159-8290 . CD-23-1186  \nThis open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.  \n©2024The Authors; Published by the American Association for Cancer Research  \nJUNE  \n2024  \nCANCER DISCOVERY | 953  \ndescribed to arise independently during embryonic development in a child with pathogenic germline variant (4) . Finally, the second malignancy may be caused by the mutagenic and/or cancer-promoting effect of the cytotoxic therapies used du","cbCaiqfARev9u4Wl","https://ap.wps.com/l/cbCaiqfARev9u4Wl","pdf",10775235,12,"English","# Abstract\n# Significance\n# Introduction\n## Embryonal cell origin and second tumors\n## Germline predisposition and mosaic somatic mutations\n## Chemotherapy-induced mutagenic effects","[{\"question\":\"Why are second malignancies in children considered extremely rare in this study?\",\"answer\":\"Children without known germline predisposing conditions developing a second malignancy during developmental ages are described as extremely uncommon.\"},{\"question\":\"How did the researchers determine the origins of the second cancers?\",\"answer\":\"They analyzed tumor and normal samples using whole-genome sequencing and error-correcting ultra-deep duplex sequencing to uncover different development routes.\"},{\"question\":\"What role did platinum-based chemotherapy play in mutation accumulation?\",\"answer\":\"Platinum-based therapies contributed at least one order of magnitude more mutations per day of exposure than aging to normal tissues in these children.\"}]","Origins of Second Malignancies in Children and Mutational Footprint of Chemotherapy in Normal Tissues - Research Brief | PDF",1789990000]