The potential of DNA modifications as biomarkers and therapeutic targets in oncology

Abstract

Knowledge of epigenetic alterations in cancer is rapidly increasing due to the development of genome-wide techniques for their identification. DNA methylation is the best understood epigenetic adaptation and disease-specific aberrant DNA methylation is a well-recognized hallmark of cancer. Recently, novel modifications, including 5-hydroxymethylation have been described, adding a new layer of complexity to understanding the epigenetic machinery and their role in cancer. There have been significant advances in techniques for the discovery and validation of DNA methylation- and hydroxymethylation-based biomarkers, each with its own advantages and limitations. With the advent of new profiling technologies, the ever-growing list of genes that show epigenetic alterations, particularly DNA methylation, emphasizes the role of these changes for early detection, diagnosis, prognosis, and prediction of response to therapies. While there are yet many challenges to the effective implementation of DNA-methylation/hydroxymethylation-based biomarkers and epigenetic therapeutics, the field is moving closer to the goal of defining personalized medicine.

Keywords:

• biomarkers
• cancer
• DNA hydroxymethylation
• DNA methylation
• epigenetic drift
• epigenetic therapy
• epigenetics
• methylation detection methods

Disclaimer

Views, opinions and endorsements by the authors do not reflect those of the Eli Lilly and Company.

Financial & competing interests disclosure

All authors are employed by Eli Lilly and Company, Indianapolis, IN, USA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Alterations in the epigenetic regulation of genome activity are as important to carcinogenesis as alterations in genome coding information itself. Aberrant DNA methylation is a well-recognized hallmark of cancer.

• High-throughput methods are important advancement and have been successfully used for candidate biomarker discovery; however, most of them are expensive and need to be improved before they can be routinely used in clinical studies.

• DNA methylation has many unique advantages for biomarker applications.

• DNA methylation biomarkers can be used to analyze tumor biopsies to guide therapeutic decisions or to interrogate body fluids about the presence of cancer.

• Relatively few DNA methylation biomarkers have been used in clinic.

• Standardization of methods, assays, reagents, and tools is critical for clinical application of DNA methylation biomarkers.

• Quantitative methodologies are essential for the identification of clinically relevant methylation biomarkers.

• There is the necessity for trials to be established to validate candidate biomarkers.

• Clinical validation of epigenetic biomarkers will be important to promote individualization of anticancer therapy.