Building Epigenetic Clocks for Estimating Ageing in Life After Cancer

Abstract

DNA methylation has been proven to be highly correlated with age. This has enabled the development of epigenetic clocks, which predicts age based on DNA methylation pattern. The predictions computed by epigenetic clocks have been interpreted to represent Biological Age, describing and pointing out the functional state of the body. The main objective of this project was to develop an epigenetic clock, and in turn use this clock to analyse differences in Biological Age between groups of testicular cancer patients 16 years after life-saving treatment. The testicular cancer patients had undergone one of two treatments: either surgery or a combination of Cisplatin-based chemotherapy and surgery. In addition, some of the patients in both treatment-groups had been diagnosed with Metabolic Syndrome. Elastic Net was used to develop epigenetic clocks based on DNA methylation samples from several data sets. Differences between groups of testicular cancer patients were analysed by applying linear regression with Residual and Intrinsic Age Acceleration as the dependent variables. The linear regression used treatment type and Metabolic Syndrome diagnosis as independent variables. Five epigenetic clocks were developed, of which one was chosen to be used in further analyses. This clock was named Aurora's clock. Aurora's clock had an RMSE of 3.1/3.8 and R2 of 0.95/0.9 in two different test sets. In addition to Aurora's clock, two previously published epigenetic clocks (eABEC and Levine DNAm PhenoAge) were used. The linear regressions indicated a lower Age Acceleration for the group treated with both Cisplatin and surgery, compared to the group treated with surgery only. The significance level varied between the clocks, with a p-value ranging from 0.03 to 0.17. All three clocks estimated a higher Age Acceleration for patients diagnosed with Metabolic Syndrome, but this was only significant when applying Levine DNAm PhenoAge (p=0.03 for Residual Age Acceleration and p=0.045 for Intrinsic Age Acceleration). This work has confirmed that Elastic Net is a well-suited algorithm for developing epigenetic clocks, as has also been shown in previously published work. It also indicates that Cisplatin-based chemotherapy does not lead to increased Age Acceleration 16 years after treatment, and that individuals diagnosed with Metabolic Syndrome may have an elevated Age Acceleration. This finding may have implications for managing patients after cancer diagnosis.