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Methylation-Based Cancer Early Detection Method Shows Promise in Preliminary Studies

NEW YORK (GenomeWeb) – Researchers at Princess Margaret Cancer Centre and the University of Toronto have developed a new methodology for the early detection of cancer via methylated DNA. Though the results need to be validated in independent samples, the researchers believe the findings could lead to new noninvasive cancer screening tests.

In a study published in a letter in Nature today, the team described an immunoprecipitation-based protocol to analyze the methylome of small quantities of circulating cell-free DNA, which could detect large-scale DNA methylation changes specific to different types of cancer, including early pancreatic tumors.

According to the authors, led by Daniel De Carvalho, a senior scientist at Princess Margaret Cancer Centre, the sensitivity and accuracy of existing blood-based cancer tests leaves much to be desired, especially for early-stage disease. Part of the reason is their reliance on DNA mutation detection.

The major obstacles to improved sensitivity include a "limited number of recurrent mutations available to distinguish between tumor and normal … in a cost-effective manner," the authors wrote, as well as the issue of technical artefacts introduced during sequencing. "We reasoned that specific enrichment of methylated DNA fragments from cfDNA could overcome both of these issues," they added.

To try to move beyond mutations, the Toronto team developed a technique to isolate, detect, and profile low levels of methylated DNA, which they call cell-free methylated DNA immunoprecipitation and high-throughput sequencing (cfMeDIP-seq).

The group is not the only academic team to investigate methylation or other epigenetic changes for early cancer detection. Numerous commercial companies in the space have also named methylation as part of their strategies, including Grail, Freenome, LAM Research's IvyGene, and Singlera.

But the Princess Margaret authors wrote that the concept still poses challenges, owing to the low abundance and fragmented nature of plasma cfDNA. This has restricted many previous blood-based methylation efforts to locus-specific PCR-based assays. And although whole-genome bisulfite sequencing has been tried by some, it presents cost and efficiency challenges.

The cfMeDIP–seq method — optimized from an existing low-input MeDIP–seq protocol — allows for the enrichment of CpG-rich, potentially more informative fragments, enhancing cost-effectiveness while avoiding the predetermination of PCR, the authors wrote.

Various experiments provided proof of principle that the approach can detect patterns of methylation that distinguish individuals with cancer from those without.

The investigators showed first that the approach could distinguish 24 early-stage pancreatic cancer patients from healthy controls. Then, in 388 samples from seven different tumor types (acute myeloid leukemia, and pancreatic, colorectal, breast, lung, renal, and bladder cancer), they demonstrated that the test could identify specific methylation profiles that don't just pick out cancer cases from healthy controls but also differentiate  the cancers.

"Our approach awaits further validation in completely independent datasets, but our findings underscore the potential utility of cfDNA methylation profiles as a basis for noninvasive, cost-effective, sensitive and accurate early tumor detection for cancer interception, and for multi-cancer classification," the team concluded.

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