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The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion

A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1–40 years. We show here that normal human...

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Detalles Bibliográficos
Autores principales: Goy, Erwan, Tomezak, Maxime, Facchin, Caterina, Martin, Nathalie, Bouchaert, Emmanuel, Benoit, Jerome, de Schutter, Clementine, Nassour, Joe, Saas, Laure, Drullion, Claire, Brodin, Priscille M, Vandeputte, Alexandre, Molendi-Coste, Olivier, Pineau, Laurent, Goormachtigh, Gautier, Pluquet, Olivier, Pourtier, Albin, Cleri, Fabrizio, Lartigau, Eric, Penel, Nicolas, Abbadie, Corinne
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8933005/
https://www.ncbi.nlm.nih.gov/pubmed/35302491
http://dx.doi.org/10.7554/eLife.67190
Descripción
Sumario:A rare but severe complication of curative-intent radiation therapy is the induction of second primary cancers. These cancers preferentially develop not inside the planning target volume (PTV) but around, over several centimeters, after a latency period of 1–40 years. We show here that normal human or mouse dermal fibroblasts submitted to the out-of-field dose scattering at the margin of a PTV receiving a mimicked patient’s treatment do not die but enter in a long-lived senescent state resulting from the accumulation of unrepaired DNA single-strand breaks, in the almost absence of double-strand breaks. Importantly, a few of these senescent cells systematically and spontaneously escape from the cell cycle arrest after a while to generate daughter cells harboring mutations and invasive capacities. These findings highlight single-strand break-induced senescence as the mechanism of second primary cancer initiation, with clinically relevant spatiotemporal specificities. Senescence being pharmacologically targetable, they open the avenue for second primary cancer prevention.