Plasma Cell-Free Tumor Methylome as a Biomarker in Solid Tumors: Biology and Applications

Abstract

DNA methylation is a fundamental mechanism of epigenetic control in cells and its dysregulation is strongly implicated in cancer development. Cancers possess an extensively hypomethylated genome with focal regions of hypermethylation at CPG islands. Due to the highly conserved nature of cancer-specific methylation, its detection in cell-free DNA in plasma using liquid biopsies constitutes an area of interest in biomarker research. The advent of next-generation sequencing and newer computational technologies have allowed for the development of diagnostic and prognostic biomarkers that utilize methylation profiling to diagnose disease and stratify risk. Methylome-based predictive biomarkers can determine the response to anti-cancer therapy. An additional emerging application of these biomarkers is in minimal residual disease monitoring. Several key challenges need to be addressed before cfDNA-based methylation biomarkers become fully integrated into practice. The first relates to the biology and stability of cfDNA. The second concerns the clinical validity and generalizability of methylation-based assays, many of which are cancer type-specific. The third involves their practicability, which is a stumbling block for translating technologies from bench to clinic. Future work on developing pan-cancer assays with their respective validities confirmed using well-designed, prospective clinical trials is crucial in pushing for the greater use of these tools in oncology.

Keywords: 5-methylcytosine; DNA methylation; biomarkers; cell-free DNA; liquid biopsy.

Figure A1

Flow diagram of search strategy of this narrative review.

Figure 1

Influence of DNA methylation on the tumor and tumor microenvironment. Cancers are characterized by extensive genomic hypomethylation that leads to chromosomal instability and oncogene activation. Focal hypermethylation of CpG islands at promoters leads to TSG silencing. Hypermethylation of gene bodies can lead to oncogene expression and alternative splicing leading to cancer-related isoforms of genes. In the tumor microenvironment DNA methylation can lead to altered immune cell fate and trafficking. DNA methylation also underpins epigenetic mechanisms of T-cell exhaustion. Created with Biorender.