Tracing Plasma DNA Origins

Not all DNA is created equal – and that’s never truer than when investigating plasma DNA that carries different genetic variants to the host constitutional genome. Now, researchers from the Chinese University of Hong Kong have developed a method called genetic-epigenetic tissue mapping (GETMap) to determine the origin of such DNA (1). GETMap is based on a comparison between the methylation profiles of plasma DNA and DNA from the potential tissue or organ of origin. In a comprehensive study, the approach was tested in pregnant women (including one who developed lymphoma during pregnancy), lung transplant patients, and liver cancer patients.

First validating the approach in pregnant women, they investigated whether GETMap could determine the tissue contributions of genetic variations in plasma DNA. They found that plasma DNA carrying fetus-specific alleles originated in the placenta, whereas maternal-specific alleles were derived from white blood cells.

Moving on, the team took on the challenge of catching allograft rejection in post-transplant patients. High levels of DNA from the transplanted organ can indicate rejection – but high levels of donor DNA are also common in the recipient’s blood immediately after surgery. To overcome this, GETMap combined genetic and epigenetic markers to determine the source of the post-transplant increase and found that, over time, lung-derived plasma DNA increased and blood cell-derived DNA decreased. They also found that patients who rejected their new lungs had higher levels of donor lung DNA than successful patients.

Using methylation profiles, the team also identified tumor mutations from plasma DNA and correctly identified the liver as the origin of the DNA molecules, creating the potential for tumor analysis in situations where biopsy is not possible or the tissue of origin is unknown.

In their final analysis, they tested a woman who developed lymphoma during pregnancy and successfully distinguished between placenta-derived fetal genes and tumor genes that originated from disease-associated white blood cells.

“We have demonstrated the powerful synergy between genetic and epigenetic approaches for identifying the origin of circulating DNA in the blood, and shown its potential applications in cancer screening, prenatal testing, and organ transplant monitoring,” said co-senior author Dennis Lo (2).