Methylation landscape as a general test for cancer

DNA methylation at the cytosine of CpG dinucleotides is a key form of epigenetic regulation of gene expression and aberrant hypermethylation of the promoter regions of certain genes has been identified in many cancers. The ability to analyse methylation status from non-invasively collected samples (such as saliva, sputum, stool and urine) as well as circulating tumour (ct)DNA in blood has led to much interest in methylation status as a potential biomarker for diagnosis, prognosis and treatment monitoring of cancer. Indeed, a fecal blood test for colorectal cancer screening (Cologuard®) that includes aberrant methylation testing of NDRG4 and BMP3 genes was approved by the Food and Drug Administration in the USA in 2014. However, methylation state analysis of specific promoter regions requires the use of technically demanding methods, such as PCR of bisulfite-treated DNA, pyrosequencing, methylation-specific PCR, methyl BEAMing and genomic sequencing, that have limitations of one sort or another in their use as high-throughput screening tools.
Recently, though, a paper by Sina et al. (“Epigenetically reprogrammed methylation landscape drives the DNA self-assembly and serves as a universal cancer biomarker” in Nature Communications 2018; 9(1): 4915) has described how the changes in methylation patterns in cancer genomes have a general effect on the physicochemical properties of DNA and that this change can be used as a potential universal cancer biomarker. In the transition from normal to malignant neoplasm, the general genomic methylation pattern changes from one of dispersed methylation to general hypomethylation but with increased clustering of methylation at regulatory regions. This change in the ‘methylation landscape’ results in a difference in the solvation properties between the normal and the cancer DNA polymer, which in turn affect the affinity of DNA to gold: the more highly aggregated normal DNA exhibits low adsorption to gold, whereas the less aggregated cancer DNA shows high adsorption. The authors have been able to use these properties to create a highly sensitive and specific, non-invasive, quick (≤10 min) colorimetric assay for the detection of cancer that needs only minimal sample preparation and small DNA input. So far, identification of this ‘Methylscape’ biomarker is only an indication of the presence of cancer – further work-up is needed to determine location, type and stage of disease. However, this seems like the ideal first test to determine whether a patient’s symptoms are caused by cancer or not.