Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies

Abstract

Understanding the relationship between aneuploidy detection on noninvasive prenatal testing (NIPT) and occult maternal malignancies may explain results that are discordant with the fetal karyotype and improve maternal clinical care.OBJECTIVE To evaluate massively parallel sequencing data for patterns of copy-number variations that might prospectively identify occult maternal malignancies. DESIGN, SETTING, AND PARTICIPANTS Case series identified from 125 426 samples submitted between February 15, 2012, and September 30, 2014, from asymptomatic pregnant women who underwent plasma cell-free DNA sequencing for clinical prenatal aneuploidy screening. Analyses were conducted in a clinical laboratory that performs DNA sequencing. Among the clinical samples, abnormal results were detected in 3757 (3%); these were reported to the ordering physician with recommendations for further evaluation.EXPOSURES NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y). MAIN OUTCOMES AND MEASURESDetailed genome-wide bioinformatics analysis was performed on available sequencing data from 8 of 10 women with known cancers. Genome-wide copy-number changes in the original NIPT samples and in subsequent serial samples from individual patients when available are reported. Copy-number changes detected in NIPT sequencing data in the known cancer cases were compared with the types of aneuploidies detected in the overall cohort.RESULTS From a cohort of 125 426 NIPT results, 3757 (3%) were positive for 1 or more aneuploidies involving chromosomes 13, 18, 21, X, or Y. From this set of 3757 samples, 10 cases of maternal cancer were identified. Detailed clinical and sequencing data were obtained in 8. Maternal cancers most frequently occurred with the rare NIPT finding of more than 1 aneuploidy detected (7 known cancers among 39 cases of multiple aneuploidies by NIPT, 18% [95% CI, 7.5%-33.5%]). All 8 cases that underwent further bioinformatics analysis showed unique patterns of nonspecific copy-number gains and losses across multiple chromosomes. In 1 case, blood was sampled after completion of treatment for colorectal cancer and the abnormal pattern was no longer evident. CONCLUSIONS AND RELEVANCEIn this preliminary study, a small number of cases of occult malignancy were subsequently diagnosed among pregnant women whose noninvasive prenatal testing results showed discordance with the fetal karyotype. The clinical importance of these findings will require further research.

Abnormal plasma DNA profiles in early ovarian cancer using a non-invasive prenatal testing platform: implications for cancer screening

“…However, the principle that tumor DNA is detectable in plasma using NIPT sequencing platforms has been previously established [2, 3]. Furthermore, the majority of genomic aberrations detected in our cases included common imbalances previously reported in a cohort of 489 HGSOC specimens [8], supporting our assumption that the DNA aberrations detected in plasma originated from ovarian tumors.…”

“…DNA libraries, prepared from cell-free DNA extracted from plasma, were sequenced on a commercial whole genome NIPT platform using the standard workflow employed for aneuploidy screening (percept™ prenatal test, Victorian Clinical Genetics Services, Parkville VIC Australia, based on Illumina’s verifi™ NIPT methodology [2]). Each research sample was sequenced alongside 14 clinical samples, with 36-cycle single-end sequencing on an Illumina NextSeq500.…”

“…Circulating DNA of tumor origin can interfere with NIPT performance and produce abnormal genomic profiles that suggest occult malignancy in pregnant women [2]. Amant et al [3] recently reported the pre-symptomatic identification of cancer in three pregnant women undergoing NIPT, suggesting that genomic profiling for copy number variations (CNVs) may be a feasible approach for cancer screening.…”

Integrative omics for health and disease

“…However, cell-free DNA for early cancer detection requires robust methods to distinguish genuine low-frequency events from sequencing errors, and single-cell sequencing is still expensive. Nonetheless, such methods have already been used to disentangle tumour heterogeneity 87 and identify a secondary finding of cancer in a prenatal test 88 . As additional omics data sets are integrated with ultra-deep sequencing, we expect the advantages of each of these methods to complement each other and provide a uniquely powerful method for molecular interrogation in the clinic.…”

Genomic profiling for copy number changes in plasma of ovarian cancer patients – a new era for cancer diagnostics?

“…This technique is successful because the amount of fetal DNA in the maternal circulation is rather high (e.g., around 5 % of total DNA). Other authors have previously shown that the use of NIPT can, in some cases, detect maternal malignancies at asymptomatic stages [7, 8]. Using NIPT sequencing data, sub-chromosomal changes (genomic gains or losses greater than 15 megabases (MB)) were considered by Cohen et al as positive indicators of malignancy.…”