Noninvasive prenatal testing clue to maternal malignancy

By Shreeya Nanda, Senior medwireNews Reporter

A preliminary study lends support to the hypothesis that a false-positive noninvasive prenatal test (NIPT) finding could be due to the presence of an occult maternal cancer.

The discordance of the NIPT results with the foetal karyotype as established by invasive diagnostic testing is “presumably due to the cfDNA [cell-free DNA] that is released into maternal circulation from apoptotic malignant cells”, says the team led by Diana Bianchi, from Tufts Medical Center in Boston, Massachusetts, USA.

Of 125,426 women who underwent plasma cfDNA sequencing over a 2.5-year period, 3% tested positive for aneuploidy in chromosomes 13, 18, 21, X or Y.

And 10 women were diagnosed with cancer at an average of 16 weeks’ post-NIPT, of whom eight were followed up as part of this study.

Diagnostic foetal karyotyping was performed in seven of the women and showed that in all cases the foetus did not have any abnormality in the number of somatic or sex chromosomes (ie, was euploid).

But comprehensive genome-wide bioinformatics analysis of cfDNA sequencing data from the eight women demonstrated copy number variations across multiple chromosomes, with a median 29% of the genome affected, and could explain the aneuploidy detected by NIPT, note the researchers.

They highlight one case where the copy number gains and losses were no longer evident once the patient reached the end of her treatment cycle for colorectal cancer.

Multiple aneuploidies were found in seven of the 10 cases of maternal cancer and in 39 of the total study sample. Among the latter, the NIPT screening findings were concordant or partially concordant with those of invasive diagnostic testing in four women, discordant in 16 and unknown in the remaining 19 women.

Bianchi et al estimate that the risk of maternal cancer as a reason for discordant NIPT results ranges from 20% to 44%, depending on whether all or none of the 19 unknown cases are discordant or not with the foetal karyotype.

They conclude in JAMA: “The data presented here underscore the necessity of performing a diagnostic procedure to determine the true fetal karyotype whenever NIPT results reveal chromosomal abnormalities.”

In a linked comment, Roberto Romero (Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA) and Maurice Mahoney (Yale University School of Medicine, New Haven, Connecticut, USA) say that the study is an “important advance” on previous work, mainly case reports and small case series, adding that more data is needed, ideally from cohort studies.

But given the difficulties involved in conducting such a study, they suggest that “[l]aboratories with similar information would provide a valuable service by sharing their experience with NIPT testing results because this may improve the accuracy of the estimates.

“Another step could be the establishment of a registry of cases with discordant NIPT results associated with multiple aneuploidies, and also with single aneuploidies, to determine maternal cancer status at the end of pregnancy and beyond.”

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