The rate at which cells in a given tissue divide is thought to determine the risk of that tissue turning cancerous. This cell-division rate is known to be influenced by cancer risk factors such as inflammation. New joint research from PICB, Shanghai, and UCL, London, published in the science journal Genome Biology provides evidence that DNA changes that accrue in normal cells as a result of life-time cell divisions could be used to predict cancer risk.
The research undertaken by Professor Andrew Teschendorff from PICB, Shanghai and UCL, used an in-silico mathematical approach to construct a “clock” which approximates the number of lifetime cell-divisions of cells in a tissue of an individual. To measure the tick-rate of this “mitotic” clock, the researchers focused on a specific chemical modification of DNA, called DNA methylation, which occurs only in specific sequences of DNA.
Previous work had shown that DNA methylation tags accrue with the chronological age of a person, allowing highly accurate prediction of the person’s age. However, such a clock can’t be used for cancer risk prediction since different organs from the same person have different propensities to develop cancer, yet they all have the same chronological age. By measuring DNA methylation at specific genomic loci, Teschendorff and his team were able to construct a different kind of clock, which does not predict chronological age, but which predicts the underlying number of stem-cell divisions in a tissue.
The authors of the current study demonstrate how the tick-rate of their mitotic clock is universally accelerated in cancer, including pre-cancerous lesions from the breast and lung, allowing, in principle, risk prediction of these cancers. Importantly, the authors further show how the tick-rate of this mitotic clock is increased in normal cells exposed to smoke carcinogens, thus linking exposure to a cancer risk factor with an increased mitotic rate mediated by inflammation.
These new findings suggest that measuring DNA methylation in a relevant cell-type could offer novel risk prediction and early detection strategies for cancer. One exciting possibility for the future is to estimate the tick-rate of this mitotic clock in cell-free DNA shed by precancerous cells in blood plasma.