Non-invasive prenatal testing: when results suggests maternal cancer

Abstract

It is now well-established that non-invasive prenatal testing (NIPT), originally designed to screen cell-free DNA (cfDNA) in maternal blood for the presence of common fetal trisomies, can lead to incidental detection of occult maternal malignancies. Retrospective evaluations have demonstrated that the detection of multiple copy number alterations in cfDNA is particularly suggestive of an incipient tumor and that cancer detection rates not only depend on tumor biology but also on applied NIPT technologies and downstream diagnostic investigations. Since the identification of a maternal cancer in pregnancy has implications for both woman and the unborn child, prospective studies are needed to provide evidence on best clinical practices and on clinical utility in terms of patient outcomes.

Keywords: Cell-free DNA; incidental finding; maternal malignancy; non-invasive prenatal testing.

Figure 1:

Detection of fetal-derived and tumor-derived copy number alterations via non-invasive prenatal testing (NIPT) during pregnancy. (A) Pregnant woman carrying a fetus with trisomy 21. During pregnancy, cell-free DNA (cfDNA) fragments are released from the placenta (green cfDNA strands) into the maternal circulation and mixed with cfDNA from maternal origin (black cfDNA strands). Upon extraction of cfDNA fragments from maternal plasma, genome-wide sequencing of these fragments and subsequent bioinformatics analysis, the presence of a fetal trisomy 21 is visible as an overrepresentation of cfDNA fragments aligning to chromosome 21 (threshold of standard deviation > 3 (z-score) indicated as dotted red line). (B) Pregnant woman with an (occult) maternal malignancy and carrying a fetus with a normal karyotype. Cell-free tumor DNA (ctDNA) fragments (yellow ctDNA strands), that represent the genetic makeup of the malignancy including chromosomal aberrations, can be shed in the maternal bloodstream. Upon genome-wide NIPT assessment for the presence of chromosomal aneuploidies in the fetus, tumor-derived CNAs will skew the signals, giving rise to an aberrant NIPT result (elevated z-scores for chromosomes 1, 2, 7, 16 and 21 (chromosome numbers indicated in red on the x-axis); vice versa, in case of a (partial) monosomy, the chromosomal z-score would drop below < –3, not depicted here). When the observed aberrations are characteristic for tumor-derived chromosomal imbalances [22] and incompatible with fetal development, a maternal malignancy might be invoked.

Figure 2:

Frequencies (%) of maternal malignancy types, inferred from NIPT. Numbers are retrieved from the large, population-based retrospective series on NIPT and detection of a maternal malignancy mentioned in Table 1.

Figure 3:

Critical elements in a multidisciplinary management model for downstream clinical investigations in pregnant women confronted with a NIPT that is suggestive of an incipient tumor.