LIVERPOOL, NOVEMBER 2017 Exposure to chemotherapy induces epigenetic damage in normal cells in childhood cancer survivors


Year:

Session type:

Theme:

Jill McKay1,Linda Sharp1,John Casement1,Gordon Strathdee1
1Newcastle University

Abstract

Background

Survival rates for many childhood cancers have improved dramatically resulting in a growing population of childhood cancer survivors (CCSs). CCSs are at increased risk of developing chronic diseases and of premature death. The mechanisms underlying these increased risks are not fully understood but epigenetic damage (such as altered DNA methylation) induced by anti-cancer therapies may be involved. We investigated whether there is evidence for genome-wide DNA methylation changes in response to therapy in normal cells from CCSs.

Method

We included paired DNA samples (from peripheral blood) from 32 children who underwent chemotherapy. The first sample was taken either at diagnosis (for those with solid tumours; n=7) or initial remission (for those with haematological malignancies; n=25) and the second at late remission (up to 2 years). Genome wide methylation analysis was performed using Illumina MethylationEpic arrays, which cover >850,000 CpG sites across the genome.

Results

After correction for false discovery rate, 146 differentially methylated regions (DMRs) were found to exhibit altered DNA methylation in normal, non-cancer, cells, in later remission compared with early remission. Changes were often large with 32 DMRs exhibiting average beta value changes of >0.1 (equivalent to 10% methylation). This suggests that exposure to chemotherapy induces large and widespread changes in DNA methylation across the genome in healthy cells. Furthermore, the induced methylation changes were similar in solid tumour and leukaemia patients, suggesting that many changes in DNA methylation occur independently of the specific cancer type or therapies used in treatment.

Conclusion

These preliminary results provide evidence for DNA methylation changes in response to anti-cancer therapy in children with cancer. Further research is required to determine if the altered DNA methylation induced is sustained into later life and whether it plays a mediating role in the development of adverse late effects in CCSs.