Detection of cancer-specific mutations in circulating tumor DNA (ctDNA) has been used to diagnose and track cancer using patient blood as a surrogate for tumor biopsies. However, in early-stage disease, the levels of ctDNA are currently too low for an accurate diagnosis. Dr. Katherine Varley and her group at the Huntsman Cancer Institute, University of Utah are looking at cancer-specific DNA methylation as a more sensitive marker of ctDNA to determine the epigenetic status of tumor DNA. Most of the current methods for assessing ctDNA methylation use sodium bisulfite conversion, which damages DNA and lowers sensitivity. Now, single-molecule third-generation sequencing allows direct detection of DNA methylation without the need for this harsh chemical modification. The technology has not yet been applied to ctDNA due to limited instrument throughput and the cost-prohibitive nature of ctDNA whole genome sequencing. Varley and her team are developing a method that captures specific areas of the genome that are modified with cancer-specific methylation, thus increasing throughput and allowing for more affordable detection of early-stage cancer. In addition, because different cancers have distinct methylation profiles, a definitive diagnosis of the cancer type may be possible. If applied broadly in the clinic, this new method could significantly reduce cancer mortality and health care costs.