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Researchers Turn Methylated DNA Profiling Method Towards Prenatal Testing Applications

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NEW YORK – A method for analyzing cell-free methylated DNA being developed for use in cancer liquid biopsy testing can potentially also be used for prenatal testing applications, according to researchers from Canada's Princess Margaret Cancer Centre (PMCC) and the University of Toronto.

"There's actually quite a bit of similarity in the DNA methylation profiles of the placenta and cancer," Samantha Wilson, a postdoc in Michael Hoffman's lab at PMCC, said in a presentation at last week's American Society of Human Genetics 2020 virtual conference. She and her colleagues hypothesized that their method, called cell-free methylated DNA immunoprecipitation sequencing (cfMeDIP-seq), would be able to enrich placental DNA from maternal plasma.

Wilson presented data on cfDNA from three maternal plasma samples taken between weeks 17 and 18 of gestation. Using principal component analysis, the team was able to separate placental from nonplacental DNA, Wilson said, based on known placenta methylome regulators, including tumor suppressors, transposon silencing elements, and placenta imprinted regions.

In addition, using synthetic spike-in controls with unique molecular indices, the researchers were able to use "generalized linear models to absolutely quantify cfDNA," Wilson said, allowing them to correct for enrichment and sequencing biases associated with fragment length, GC content, and CpG dinucleotide fraction within a fragment.

Wilson hopes to advance the method by combining it with machine-learning algorithms to predict preterm birth.

Published in 2018, cfMeDIP-seq uses antibodies to pull out small quantities of methylated, circulating, cell-free DNA. The method avoids the chemical conversion and destructive nature of bisulfite sequencing, the gold-standard method for methylation profiling. Moreover, it may be cheaper than whole-genome bisulfite sequencing. In proof-of-concept studies, the method's developers showed that they could detect methylation patterns indicative of several different cancers.

In January 2019, Wilson and her colleagues won a five-year, C$1.2 million ($915,000) grant from the Canadian Institutes of Health Research to develop a noninvasive method to screen for pre-term birth.

"In this study, we will look at the chemical changes found between circulating DNA of healthy pregnancies and pregnancies involving premature birth … We will identify changes in DNA methylation that can determine pregnancies with a high risk of premature birth. Since the test only uses DNA in the mother's blood, we can do this with a noninvasive blood test with little additional risk to the pregnancy," the researchers wrote in their grant abstract. "This study will result in a noninvasive blood test that can detect pregnancies with increased risk of premature delivery. Use of this test will lead to changes in pregnancy care to try to prevent premature birth."

In her ASHG talk last week, Wilson said the team is in the process of collecting 300 patient samples representing preterm births and healthy controls. Using cfMeDiP-seq and machine learning, she and her colleagues hope to be able to predict subtypes of preterm birth, as well as early and late preeclampsia.

CfMeDIP-seq is not a "be-all-and-end-all technique," Wilson cautioned. It doesn't profile all placental DNA, only hypermethylated regions, and it can't yet reach single-base resolution. Moreover, it can't yet fully disentangle placental DNA from maternal DNA. "We're working on deconvoluting this," she added.

But the method is noninvasive, can be used across gestation, and can obtain DNA sequence information — potentially even single-nucleotide variants.

In July, PMCC announced that it was spinning out DNAMx, a startup that plans to commercialize cfMeDIP-seq. In addition to its use in cancer liquid biopsy testing, "the platform also holds promise for application to conditions beyond cancer detection including prenatal diagnostics, cardiology, and monitoring of immune responses," PMCC said in a statement. "DNAMx has secured experienced executives to spearhead its first round of financing, which will trigger the license and bring the technology closer to patients on a global scale." PMCC and researchers involved with the company declined to discuss the firm's plans at this time.

In her ASHG talk, Wilson disclosed that she is an inventor on a provisional patent application for "synthetic spike-in controls for cell-free MeDIP sequencing and methods of using same."

Wilson said she has hope she can develop the method into a clinically useful test. "Currently we're sequencing everything, and it's expensive," she said. "If we find a machine learning model that is able to predict preterm birth or whatever pregnancy complication we're looking at, the next step is to reduce the dimensions in the data and create a panel that would be more cost effective for a healthcare setting."

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