• Fetal Circulating Tumor DNA in Maternal Blood: Expanding Noninvasive Prenatal Testing to Early Cancer Detection
  • Zahra Dahaghin,1,*
    1. Department of Laboratory Sciences, School of Paramedical Sciences, Hamadan University of Medical Sciences, Hamadan, Iran


  • Introduction: Cell-free DNA (cfDNA) refers to fragments of nucleic acids circulating freely in plasma, serum, and other body fluids outside of cells. This phenomenon was first described by Mandel and Metais in 1948(1).cfDNA originates from apoptotic, necrotic, and secretory pathways, producing a complex circulating profile with clinical utility in cancer diagnostics, prenatal testing, and disease monitoring. Maternal cfDNA has a modal length of 166–167 bp, whereas fetal cfDNA fragments are shorter, around 143–145 bp. In malignant fetal conditions, fetal circulating tumor DNA (ctDNA) is even more fragmented, commonly enriched between 90–150 bp, with fragments as short as 134–144 bp. Such fragment size enrichment is a hallmark of ctDNA and is exploited in clinical assays to improve sensitivity for tumor detection. Fragment periodicity (~10 bp), reflecting nucleosomal structure, is also observed in both fetal and tumor-derived cfDNA(2-5).Liquid biopsy leverages cfDNA to obtain minimally invasive information about tumors. Blood is the most commonly used source, though cfDNA is detectable in urine, cerebrospinal fluid, pleural effusion, and ascitic fluid. Analysis of genetic and epigenetic alterations, including mutations and methylation, provides clinically relevant insights(6-8).
  • Methods: Since the late 1970s, ctDNA has been extensively quantified and characterized across cancer types, supporting early detection, treatment monitoring, and assessment of residual disease(9-14).Fetal cfDNA appears in maternal blood as early as 4–7 weeks of gestation and increases steadily throughout pregnancy. The fetal fraction, typically ~10% at 11–13 weeks, rises gradually, enabling reliable noninvasive prenatal testing (NIPT) around 7–10 weeks. After delivery, fetal cfDNA is rapidly cleared within hours(15).Fetal ctDNA is extracted from maternal plasma using phenol-chloroform extraction, silica-based spin columns, or magnetic beads. Sensitive techniques, including quantitative PCR (qPCR), droplet digital PCR (ddPCR), and next-generation sequencing (NGS), enable accurate detection of genetic alterations despite low fetal ctDNA abundance(28-31).
  • Results: NIPT based on cfDNA screens for fetal chromosomal abnormalities. Recent studies indicate cfDNA can also reveal malignancies. Fetal ctDNA in maternal plasma may serve as a noninvasive biomarker for early detection of fetal malignancies. Detecting abnormal genetic alterations without invasive procedures allows earlier diagnosis, timely intervention, improved fetal outcomes, and reduced procedural risks. Confirmatory testing and maternal evaluation remain necessary, expanding prenatal cfDNA testing beyond genetic disorders to include malignancy detection(16-20). Advanced techniques enable fetal ctDNA analysis. Maternal plasma is examined for unusual copy number changes or somatic mutations indicative of fetal cancer. These methods avoid invasive procedures like amniocentesis. Most clinical experience involves incidental maternal cancer detection, but the same principles apply to fetal malignancies. Multidisciplinary care and confirmatory testing guide management. Ongoing development of sequencing platforms and bioinformatics improves sensitivity and specificity(21, 22). Challenges remain. The fetal ctDNA fraction is often low compared to maternal cfDNA, complicating detection in early gestation or small tumor burdens. Technical limitations include assay sensitivity, biological noise, maternal copy number variations, multiple gestations, and absence of heterozygosity, which can produce false positives or negatives. Improvements in fragmentomics, sequencing, and combined analytical strategies aim to overcome these obstacles(23-27).
  • Conclusion: This poster highlights fetal ctDNA in maternal blood as a noninvasive biomarker for early detection of fetal malignancies, emphasizing its role in expanding prenatal screening beyond genetic abnormalities. Integration into prenatal care preserves NIPT advantages while enabling early identification of rare fetal cancers. Early detection facilitates timely intervention, improves fetal outcomes, and supports precision prenatal medicine.
  • Keywords: Cell-free DNA Circulating tumor DNA Fetal malignancy Noninvasive prenatal testing Liquid biopsy