The incidence of cancer is continuing to rise and risk-tailored early diagnostic and/or primary prevention strategies are urgently required. The ideal risk-predictive test should: integrate the effects of both genetic and nongenetic factors and aim to capture these effects using an approach that is both biologically stable and technically reproducible; derive a score from easily accessible biological samples that acts as a surrogate for the organ in question; and enable the effectiveness of risk-reducing measures to be monitored. Substantial evidence has accumulated suggesting that the epigenome and, in particular, DNA methylation-based tests meet all of these requirements. However, the development and implementation of DNA methylation-based risk-prediction tests poses considerable challenges. In particular, the cell type specificity of DNA methylation and the extensive cellular heterogeneity of the easily accessible surrogate cells that might contain information relevant to less accessible tissues necessitates the use of novel methods in order to account for these confounding issues. Furthermore, the engagement of the scientific community with health-care professionals, policymakers and the public is required in order to identify and address the organizational, ethical, legal, social and economic challenges associated with the routine use of epigenetic testing.

Breast Center Department of Gynaecology and Obstetrics University of Munich Munich Germany

Center for Medical Decision Sciences Department of Public Health Erasmus MC Rotterdam Netherlands

Centre of Genomics and Policy McGill University Montreal Canada

Department of Applied Health Research Institute of Epidemiology and Healthcare University College London UK

Department of Biomedical Data Sciences LUMC Leiden Netherlands

Department of Health Sciences University of Leicester Leicester UK

Department of Laboratory Medicine Karolinska Institutet Stockholm Sweden

Department of Medical Ethics and Philosophy of Medicine Erasmus Medical Center Rotterdam Netherlands

Department of Non communicable Disease Epidemiology London School of Hygiene and Tropical Medicine London UK

Department of Obstetrics and Gynaecology 1st Medical Faculty of the Charles University and General Faculty Hospital Prague Czech Republic

Department of Obstetrics and Gynecology Haukeland University Hospital and Centre for Cancer Biomarkers Department of Clinical Science University of Bergen Bergen Norway

Department of Women's Cancer Institute for Women's Health University College London London UK

European Institute of Oncology and University Milan Bicocca Milan Italy

Harvard T C Chan School of Public Health Center for Health Decision Science Department of Health Policy and Management Boston MA USA

Institute of Public Health Medical Decision Making and Health Technology Assessment Department of Public Health Health Services Research and HTA UMIT University for Health Sciences Medical Informatics and Technology Hall in Tirol Austria

Karolinska University Laboratory Karolinska University Hospital Stockholm Sweden

Max Planck Institute for Human Development Center for Adaptive Rationality Berlin Germany

Max Planck Institute for Human Development Harding Center for Risk Literacy Berlin Germany

Oncotyrol Center for Personalized Medicine Innsbruck Austria

Public Population Project in Genomics and Society McGill University and Genome Quebec Innovation Centre Montreal Canada

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