Selective pressures of platinum compounds shape the evolution of therapy-related myeloid neoplasms.
Humans
Tumor Suppressor Protein p53
/ genetics
Li-Fraumeni Syndrome
/ genetics
Child
Germ-Line Mutation
Neoplasms, Second Primary
/ genetics
Male
Female
Platinum Compounds
/ therapeutic use
Adult
Adolescent
Whole Genome Sequencing
Phylogeny
Child, Preschool
Antineoplastic Agents
/ therapeutic use
Single-Cell Analysis
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 Jul 2024
17 Jul 2024
Historique:
received:
12
06
2023
accepted:
08
07
2024
medline:
18
7
2024
pubmed:
18
7
2024
entrez:
17
7
2024
Statut:
epublish
Résumé
Therapy-related myeloid neoplasms (t-MN) arise as a complication of chemo- and/or radiotherapy. Although t-MN can occur both in adult and childhood cancer survivors, the mechanisms driving therapy-related leukemogenesis likely vary across different ages. Chemotherapy is thought to induce driver mutations in children, whereas in adults pre-existing mutant clones are selected by the exposure. However, selective pressures induced by chemotherapy early in life are less well studied. Here, we use single-cell whole genome sequencing and phylogenetic inference to show that the founding cell of t-MN in children starts expanding after cessation of platinum exposure. In patients with Li-Fraumeni syndrome, characterized by a germline TP53 mutation, we find that the t-MN already expands during treatment, suggesting that platinum-induced growth inhibition is TP53-dependent. Our results demonstrate that germline aberrations can interact with treatment exposures in inducing t-MN, which is important for the development of more targeted, patient-specific treatment regimens and follow-up.
Identifiants
pubmed: 39019934
doi: 10.1038/s41467-024-50384-z
pii: 10.1038/s41467-024-50384-z
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
TP53 protein, human
0
Platinum Compounds
0
Antineoplastic Agents
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
6025Subventions
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
ID : 864499
Informations de copyright
© 2024. The Author(s).
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