DNA hypomethylation in plasma as a cancer biomarker: when less is more?

Evaluation of: Chan KC, Jiang P, Chan CW et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc. Natl Acad. Sci. U.S.A. 110(47), 18761–18768 (2013).Early cancer detection strategies are required to identify patients at initial stages, when curative-intended treatment is more effective. Assessment of genome-wide hypomethylation might allow for early cancer detection in bodily fluids, but requires high throughput technologies, such as next generation sequencing. In the study under evaluation, performance of a hypomethylation and copy number aberration (CNA) assay for detection of hepatocellular carcinoma (HCC), based on massive parallel bisulfite sequencing of plasma DNA was assessed. Sensitive (92/69%) and specific (88/94%) HCC detection (using 'OR'/'AND' algorithms) was achieved using a mean sequencing depth of 93 million reads in one lane. Using the 'AND' or the 'OR' algorithms, other cancer types were detected with 60% sensitivity and 94% specificity, or 85% sensitivity and 88% specificity, respectively. Lowering sequencing depth to 10 million reads (decreasing analysis time and cost) did not alter hypomethylation performance but impaired that of CNA.