Unusual Prenatal Genomic Results Provide Proof-of-Principle of the Liquid Biopsy for Cancer Screening

A best-selling book, entitled, “What to Expect When You're Expecting,” has provided reassuring information to several generations of pregnant women (1). Filled with advice on topics such as nutrition and morning sickness, it lacks a chapter on being diagnosed with cancer during pregnancy. Why would it even have such a chapter? Pregnant women represent the epitome of good health and the promise of new life. No one expects to be diagnosed with cancer while pregnant. Yet, as Dharajiya and colleagues demonstrate in this issue of Clinical Chemistry (2), incidental detection of maternal neoplasia is possible while performing prenatal whole genome DNA sequencing to screen for fetal chromosomal aneuploidies. Not only is it possible, it is not uncommon. It is also creating new ethical and clinical dilemmas. These investigators described 55 maternal plasma samples sequenced over a 3-year period in a large-scale clinical laboratory that had altered genome profiles and were suspicious for maternal neoplasm. Of these, 43 of 55 (78.1%) had certain clinical follow-up information available. Forty of 43 had confirmed maternal neoplasms; half were due to uterine leiomyomas and half were due to a variety of malignant tumors. Of these, 7 of 20 were already diagnosed, but 13 women who were expecting information about their fetus instead received the worrisome news that their plasma DNA profile put them at risk for cancer. Starting in 2011, analysis of circulating cell-free DNA (cfDNA) in the blood of pregnant women began to be offered clinically as a prenatal screen for trisomies 13, 18, and 21 (3). Owing to its superior sensitivity and positive predictive values compared to serum biochemistry and ultrasound markers, the cfDNA test became rapidly incorporated into prenatal clinical care. By 2013, however, reports began to appear that described examples of false-positive test results (4). Experts questioned the methodologies used …