Anti-cancer therapy is associated with long-term epigenomic changes in childhood cancer survivors

Natassia Robinson, John Casement, Marc J Gunter, Inge Huybrechts, Antonio Agudo, Miguel Rodríguez Barranco, Fabian Eichelmann, Theron Johnson, Rudolf Kaaks, Valeria Pala, Salvatore Panico, Torkjel M Sandanger, Matthias B Schultze, Ruth C Travis, Rosario Tumino, Paolo Vineis, Elisabete Weiderpass, Roderick Skinner, Linda Sharp, Jill A McKayGordon Strathdee*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Background: Childhood cancer survivors (CCS) exhibit significantly increased chronic diseases and premature death. Abnormalities in DNA methylation are associated with development of chronic diseases and reduced life expectancy. We investigated the hypothesis that anti-cancer treatments are associated with long-term DNA methylation changes that could be key drivers of adverse late health effects. Methods: Genome-wide DNA methylation was assessed using MethylationEPIC arrays in paired samples (before/after therapy) from 32 childhood cancer patients. Separately, methylation was determined in 32 samples from different adult CCS (mean 22-years post-diagnosis) and compared with cancer-free controls (n = 284). Results: Widespread DNA methylation changes were identified post-treatment in childhood cancer patients, including 146 differentially methylated regions (DMRs), which were consistently altered in the 32 post-treatment samples. Analysis of adult CCS identified matching methylation changes at 107/146 of the DMRs, suggesting potential long-term retention of post-therapy changes. Adult survivors also exhibited epigenetic age acceleration, independent of DMR methylation. Furthermore, altered methylation at the DUSP6 DMR was significantly associated with early mortality, suggesting altered methylation may be prognostic for some late adverse health effects in CCS. Conclusions: These novel methylation changes could serve as biomarkers for assessing normal cell toxicity in ongoing treatments and predicting long-term health outcomes in CCS.

Original languageEnglish
Pages (from-to)288-300
Number of pages13
JournalBritish Journal of Cancer
Volume127
Issue number2
Early online date30 Mar 2022
DOIs
Publication statusPublished - 20 Jul 2022

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