When given the option, a pregnant woman is more likely to prefer a peripheral blood draw over an amniocentesis or chronic villi sampling for prenatal testing for fetal disorders. Yuk-Ming Dennis Lo, MD, director of the Li Ka Shing Institute of Health Sciences and the Li Ka Shing Professor of Medicine at The Chinese University of Hong Kong conducted groundbreaking research that has made a peripheral blood draw a clinically viable option for many pregnant women. Sunday’s opening plenary speaker and 2015 AACC Wallace H. Coulter Lectureship Award recipient, Lo offered fresh insights on why circulating cell-free nucleic acids in plasma are a treasure trove for research, and how he envisions clinical applications in the 21st century.
Lo detailed his laboratory’s findings from 1997 to the present that demonstrated maternal plasma contained cell-free fetal DNA and the diagnostic and prognostic capabilities of this material. Fragments released by apoptotic cells are thought to be the major source of cell-free nucleic acids. Dr. Lo discussed how the medical community has come to embrace using maternal plasma as the sample of choice for the detection of a myriad of fetal disorders, while transitioning away from using the conventional amniocentesis fluid. He provided an overview of the techniques employed to detect cell-free fetal DNA, including PCR, massively parallel genomic sequencing, and genomewide bioinformatics analysis.
Lo also noted the importance of optimal testing protocols and the effects of pre-analytical factors on the stability cell-free nucleic acids. “Over 60 countries worldwide utilize non-invasive prenatal screening, and over the last 4 years an estimated 1 million tests have been performed,” Lo said.
He provided other examples of potential clinical uses for circulating plasma DNA. Using nasopharyngeal carcinoma (NPC), a relatively common cancer in Southeast Asia as an example, he described a plasma DNA method pioneered by his laboratory that quantitates the concentration of Epstein-Barr virus DNA. The method was useful in the early detection of NPC in patients without any definitive clinical symptoms of NPC, monitoring of the tumor and prognosis (Cancer 2013;119:1838–44). Lo also described recent exciting work from his laboratory on using genomewide plasma DNA sequencing as a universal approach for cancer detection and monitoring.
Lo also outlined a new approach for plasma DNA-based molecular diagnostics that is dependent on the analysis of DNA fragment size. He reported data showing that, intriguing, fetal DNA and tumor DNA molecules in plasma are shorter than the background DNA molecules in plasma from a pregnant mother and from the non-neoplastic tissues in a cancer patient, respectively. Lo illustrated exciting new possibilities for prenatal and cancer testing using this approach.
Lo showed that DNA-protein interactions appear to be an important determinant of the size of circulating DNA molecules. This line of thought has led him to study the size of circulating DNA in systemic lupus erythematosus (SLE), a disorder which has the hallmark of anti-DNA binding antibodies. Lo demonstrated the interesting results showing that the more active the SLE disease activity is, the shorter is the plasma DNA molecules. His laboratory is interrogating the clinical significance of these results for developing predicative models that will help monitor SLE patients.
The future of cell-free DNA testing on the molecular field seems limitless. Close collaborations between clinicians with problems to solve, scientists with expertise in cutting edge molecular techniques and bioinformaticians with knowhow on genome-scale data analysis are essential to push the field forward.