Origins of second malignancies in children and mutational footprint of chemotherapy in normal tissues

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  • dc.contributor.author Sánchez-Guixé, Mònica
  • dc.contributor.author Muiños, Ferran
  • dc.contributor.author Pinheiro Santin, Morena
  • dc.contributor.author González-Huici, Víctor
  • dc.contributor.author Rodriguez-Hernandez, Carlos J
  • dc.contributor.author Avgustinova, Alexandra
  • dc.contributor.author Lavarino, Cinzia
  • dc.contributor.author González-Pérez, Abel
  • dc.contributor.author Mora, Jaume
  • dc.contributor.author López Bigas, Núria
  • dc.date.accessioned 2025-03-27T06:46:21Z
  • dc.date.available 2025-03-27T06:46:21Z
  • dc.date.issued 2024
  • dc.description.abstract Pediatric cancers are rare diseases, and children without known germline predisposing conditions who develop a second malignancy during developmental ages are extremely 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.
  • dc.description.sponsorship N. Lopez-Bigas acknowledges funding from the European Research Council (consolidator grant 682398). M. Sanchez-Guixe was supported by a postdoctoral contract with the Centro de Investigación Biomédica en Red de Cáncer (CIBERONC). This project was supported by the PID2021-126568OB-I00 (CHEMOHEALTH) project, funded by the Spanish Ministry of Science (MCIN), AEI 10.13039/501100011033/. It has also been supported by the project “Discovering the molecular signatures of cancer PROMotion to INform prevENTion” (PROMI­NENT) funded by Cancer Research UK (CGCATF-2021/100008), NCI (1OT2CA278668-01) and the Spanish Cancer Association, AECC. IRB Barcelona is a recipient of a Severo Ochoa Centre of Excellence Award from the Spanish Ministry of Economy and Competitiveness (MINECO; Government of Spain) and an Excellence Institutional grant by the Asociacion Española contra el Cancer, and is supported by CERCA (Generalitat de Catalunya). We are grateful to the Band of Parents at Hospital Sant Joan de Déu Barcelona for supporting the overall research activities of the developmental tumor laboratory, PCCB, and for having generously contributed with their samples. This study would have been impossible to reach without this contribution.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Sánchez-Guixé M, Muiños F, Pinheiro-Santin M, González-Huici V, Rodriguez-Hernandez CJ, Avgustinova A, et al. Origins of second malignancies in children and mutational footprint of chemotherapy in normal tissues. Cancer Discov. 2024 Jun 3;14(6):953-64. DOI: 10.1158/2159-8290.CD-23-1186
  • dc.identifier.doi http://dx.doi.org/10.1158/2159-8290.CD-23-1186
  • dc.identifier.issn 2159-8274
  • dc.identifier.uri http://hdl.handle.net/10230/70021
  • dc.language.iso eng
  • dc.publisher American Association for Cancer Research (AACR)
  • dc.relation.ispartof Cancer Discov. 2024 Jun 3;14(6):953-64
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/682398
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PE/PID2021-126568OB-I00
  • dc.rights © 2024 The Authors; Published by the American Association for Cancer Research This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
  • dc.subject.other Càncer en els infants
  • dc.subject.other Tumors
  • dc.title Origins of second malignancies in children and mutational footprint of chemotherapy in normal tissues
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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