DNA methylation ageing clocks and pancreatic cancer risk: pooled analysis of three prospective nested case-control studies.

DNA methylation (DNAm) age may reflect age-related variations in biological changes and abnormalities related to ageing. DNAm age acceleration measures have been associated with a number of cancers, but to our knowledge, have not been examined in relation to pancreatic cancer risk or survival. DNAm levels in leukocytes of prediagnostic blood samples of 393 pancreatic cancer cases and 431 matched controls, pooled from three large prospective cohort studies, were used to estimate DNAm age, epigenetic age acceleration (AA), and intrinsic epigenetic age acceleration (IEAA) metrics. Logistic regression and Cox proportional hazard regression models were used to examine the relationship between the various AA and IEAA metrics and pancreatic cancer risk and survival, respectively. The results showed that pancreatic cancer risk was significantly increased across all IEAA metrics, ranging from 83% to 95% increased risk when comparing the third and highest quartiles to the lowest quartile of IEAA. Consistent with these findings, the results from multivariate spline regression analyses showed non-linear relationships between all three IEAA metrics and pancreatic cancer risk with apparent threshold effect including two turning points at minimal and at maximal risks, respectively. There is no evidence of a significant association between pancreatic cancer survival and any of the epigenetic AA or IEAA metrics. Our results indicate DNAm age acceleration, measured in blood prior to cancer diagnosis, is associated with an increased risk of pancreatic cancer in a complex nonlinear, dose-response manner. Epigenetic IEAA metrics may be a useful addition to current methods for pancreatic cancer risk prediction.