Four new papers co-published by an international consortium demonstrate and further the clinical potential of epigenetic assays. The series of manuscripts was led by Christoph Bock (CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences) and Stephan Beck (University College London).
Comparison of DNA Methylation Assays Suited for the Clinic
While there are a number of fancy methods to analyze DNA methylation that could be used routinely in the clinic, a much needed comparison has not been made. In the first study, published in Nature Biotechnology and coordinated by CeMM, 18 research groups from three continents compared the clinical potential of commonly used methods for analyzing DNA methylation.
The international team compared assays that measure:
- Absolute DNA methylation:
- Amplicon bisulfite sequencing (AmpliconBS).
- Enrichment bisulfite sequencing (EnrichmentBS).
- Mass spectrometric analysis (EpiTyper).
- Bisulfite pyrosequencing.
- Relative DNA methylation:
- Methylation-specific melting assays, including methylation-sensitive high-resolution melting (MS-HRM) and methylation-specific melting curve analysis (MS-MCA).
- Quantitative methylation-specific PCR (qMSP).
- Global methylation:
- High-performance liquid chromatography followed by mass spectrometry (HPLC-MS).
- Immunoquantification of global DNA methylation (Immunoquant).
- Bisulfite pyrosequencing of repetitive DNA elements (AluYb8/D4Z4/LINE/NBL2).
The locus-specific (absolute and relative) assays greatly outperformed global assays. By selecting tricky CpGs from the 450K array as comparison points, the locus-specific technologies were quantitatively compared. The verdict? Absolute assays beat relative assays. Furthermore, amplicon bisulfite sequencing and bisulfite pyrosequencing have the best all-around performance and were closely followed by EpiTyper. However, the clinical insight doesn’t end here as there are 3 accompanying papers.
Diving Deeper into the Methylome
Two of the papers in this series are from University College London and further investigate DNA methylation.
- In Nature Biotechnology, the team presents a computational validation of genome-wide DNA methylation sequencing technology, confirming its practical use for identifying DNA methylation differences between samples and disease subtypes.
- The team further extended their analysis in a paper published in Nature Communications, where they present new bioinformatic methods for discovering disease-specific DNA methylation patterns from cost-effective low-coverage DNA methylation sequencing data.
Stephan Beck summarizes, “This exciting new technology will advance our ability to understand phenotypic plasticity in health and disease, an important aspect of cancer research.”
Finally, a Nature Communications paper by CeMM researchers – in collaboration with the clinicians at the University of Southampton and the Royal Bournemouth Hospital – demonstrates the utility of chromatin mapping by ATAC-seq for identifying disease subtypes and predicting prognosis in chronic lymphocytic leukemia. This study highlights the clinical utility of epigenetic biomarkers especially for diseases with widespread heterogeneity between individual patients.
Christoph Bock shares, “Epigenetic tests have a key role to play for making precision medicine a clinical reality. Epigenetics captures part of each cell’s individual history, and it can predict how cancer cells will react to drug treatment. This can be very useful for personalized therapy.”
The Clinical Future of Personalized Epigenomics
Giulio Superti-Furga (Scientific Director of CeMM) concludes, “It is part of CeMM’s mission to provide innovative platforms for precision medicine and to make them ready for biomedically important applications. We are proud of the work that Christoph Bock has done together with Stephan Beck and members of the BLUEPRINT consortium. It shows that epigenetics bridges genomics and disease.” Ultimately, when considered together, these studies suggest that, with some future optimization, epigenetic assays targeting informative regions will be coming to a clinic near you.