Current status of development of methylation biomarkers for in vitro diagnostic IVD applications

Abstract

A significant volume of research clearly shows that disease-related methylation changes can be used as biomarkers at all stages of clinical disease management, including risk assessment and predisposition screening through early diagnostics to personalization of patient care and monitoring of the relapse and chronic disease. Thus diseaserelated methylation changes are an attractive source of the biomarkers that can have significant impact on precision medicine. However, the translation of the research findings in methylation biomarkers field to clinical practice is at the very least not satisfactory. That is mainly because the evidence generated in research studies indicating the utility of the disease-related methylation change to predict clinical outcome is in majority of the cases not sufficient to postulate the diagnostic use of the biomarker. The research studies need to be followed by well-designed and systematic investigations of clinical utility of the biomarker that produce data of sufficient quality to meet regulatory approval for the test to be used to make clinically valid decision. In this review, we describe methylation-based IVD tests currently approved for IVD use or at the advanced stages of the development for the diagnostic use. For each of those tests, we analyze the technologies that the test utilizes for methylation detection as well as describe the types of the clinical studies that were performed to show clinical validity of the test and warrant regulatory approval. The examples reviewed here should help with planning of clinical investigations and delivery of the clinical evidence required for the regulatory approval of potential methylation biomarker based IVD tests.

Circulating Cell-Free DNA Methylation Profiles in the Early Detection of Ovarian Cancer: A Scoping Review of the Literature

“…This is concordant with both our results and studies in ovarian and other cancers showing that utilizing multimodal methods and algorithms provides improved screening and diagnostic performances [ 7 , 9 , 48 ]. Indeed, non-invasive methylation-based biomarker tests that are currently commercially available for various cancers tend to be panels that target multiple genes [ 17 , 49 , 50 ].…”

Development of a Liquid Biopsy Based Purely Quantitative Digital Droplet PCR Assay for Detection of MLH1 Promoter Methylation in Colorectal Cancer Patients

“…In addition, global hypomethylation of the human genome paired with CpG islands of hypermethylation, allow for a minimal number of loci to be targeted and yet have sufficient test coverage [16]. These features make cancer-associated DNA methylation changes an attractive source for clinical biomarker discovery [17,18]. Therefore, targeting DNA methylation changes as cancer biomarkers hold potential for detection and minimal residual disease.…”

DNA Methylation in Solid Tumors: Functions and Methods of Detection

“…They usually control tissue-specific genes and methylation of CpGs inside these promoters was also shown to influence gene expression [ 28 ]. Moreover, if the targets of analysis are known and routinely analyzed, there is a number of validated and registered kits for methylation detection [ 29 , 30 ]. Moreover, the quality and quantity of input DNA, sensitivity and specificity of the chosen method, cost per sample, and availability of equipment plays an important role in the decision process.…”