Challenges in promoter methylation analysis in the new era of translational oncology: a focus on liquid biopsy

Toward the discovery of novel reliable biomarkers, epigenetic alterations have been repeatedly proposed for the diagnosis and the development of therapeutic strategies against cancer. Indeed, for promoter methylation to actively become a tumor marker for clinical use, it must be combined with a highly informative technology evaluated in an appropriate biospecimen. Methodological standardization related to epigenetic research is, in fact, one of the most challenging tasks. Moreover, tissue-based biopsy is being complemented and, in some cases, replaced by liquid biopsy. This review will highlight the advancements made for both pre-analytical and analytical implementation for the prospective use of methylation biomarkers in clinical settings, with particular emphasis on liquid biopsy. •Translational oncology is relying on methylation-based biomarkers for early diagnosis, to predict response to therapy and the onset of relapse;•DNA methylation can convey valuable insights about the course of the disease, thus being considered as a bio-archive;•A wide range of methods has been employed to assess promoter methylation, either dependent or independent on bisulfite conversion.•The analysis of promoters methylation on ctDNA represents a truly promising test to be performed in addition to or in lieu of tissue biopsies;•There is a need for standardization of methods that utilize epigenetics biomarkers for cancer patients' care prior to clinical implementation.