A new liquid biopsy test can accurately detect aberrant cancer-associated methylation patterns from minute amounts of DNA shed into the bloodstream. Although prospective validation is still needed, two studies highlight the assay's potential to noninvasively classify brain and kidney tumors.

A new liquid biopsy test can accurately detect aberrant cancer-associated methylation patterns from minute amounts of cell-free DNA (cfDNA) without requiring ultra-deep sequencing or prior knowledge of patient-specific tumor aberrations.

Although prospective validation is needed, two studies published in June highlight the blood test's potential to noninvasively classify brain and kidney tumors. A company called DNAMx aims to commercialize the assay as a prognostic test or a monitoring tool for disease recurrence following treatment of localized tumors.

The diagnostic is based on a platform called cfMeDIP-seq, first described in 2018 by Daniel De Carvalho, PhD, and his colleagues at Princess Margaret Cancer Centre in Toronto, Canada (Nature 2018;563:579–83). Short for cell-free methylated DNA immunoprecipitation and high-throughput sequencing, cfMeDIP-seq takes advantage of affinity capture methods to enrich blood samples for highly methylated regions of the genome known as CpG sites. After sequencing the captured fragments of cfDNA, the platform uses machine-learning algorithms to detect and classify tumors.

Unlike other methylation profiling techniques—including the targeted bisulfite sequencing approach being advanced by GRAIL—cfMeDIP-seq does not involve a conversion step that can lead to significant loss of genetic material (Ann Oncol 2020;31:745–59). Nor does it require extensive discovery studies to find regions of the genome likely to be epigenetically informative.

“The technique checks all the boxes for what researchers want from a methylation assay that is suited for cfDNA,” says Ruben Van Paemel, MD, of Ghent University in Belgium, who was not involved in the research. “It works with very low quantities of fragmented DNA, has an acceptable cost, and has a turnaround time that could be compatible with real-time clinical decision-making.”

In one new study, a team led by De Carvalho and Gelareh Zadeh, MD, PhD, of Toronto Western Hospital's Krembil Neuroscience Centre, generated cfMeDIP-seq profiles on plasma samples from patients with a variety of brain cancers, including gliomas, meningiomas, hemangiopericytomas, and neuronal–glial tumors (Nat Med 2020;26:1044–7). Not only could the platform distinguish brain tumors from extracranial cancer types and healthy controls, but it could also discriminate between different tumors of the central nervous system that often look indistinguishable on a brain scan.

Such a blood-based test could improve neurosurgical planning and reduce the need for invasive biopsies to establish diagnoses, says De Carvalho, who cofounded DNAMx with his Princess Margaret colleague Scott Bratman, MD, PhD.

In the second study, De Carvalho teamed up with researchers at Dana-Farber Cancer Institute in Boston, MA, to determine whether cfMeDIP-seq could help catch early signs of renal cell carcinoma, a cancer that sheds little cfDNA (Nat Med 2020;26:1041–3). The assay distinguished cancer-free control subjects from those with early-stage kidney tumors with near-perfect precision.

With an eye to even less invasive testing, the Dana-Farber team—led by Toni Choueiri, MD, and Matthew Freedman, MD—also tried the technique on urine from patients. The method proved less accurate than when testing blood, but the authors believe that certain improvements to cfMeDIP-seq could boost its precision for urinalysis.

Jason Ross, PhD, of the Commonwealth Scientific and Industrial Research Organisation in North Ryde, Australia, applauds De Carvalho and his colleagues for applying cfMeDIP-seq to clinical situations in which conversion techniques might lead to complete loss of measurable signals. “By going after tumors where the circulating tumor DNA is exceptionally rare,” he says, “the authors for these two papers have identified areas where [cfMeDIP-seq] has distinct advantages” over other epigenetic liquid biopsy approaches.

At the American Association for Cancer Research Virtual Annual Meeting II in June, De Carvalho also discussed unpublished research showing that the presence of cfDNA, as measured by cfMeDIP-seq, strongly correlated with recurrence-free survival after surgery and radiation therapy among patients with localized head and neck tumors. He presented similar data linking overall survival and cfMeDIP-seq test results in patients with prostate cancer.

“We can track the response to therapy quite well,” De Carvalho says. “I think there's huge potential there.” –Elie Dolgin

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