Abstract
Background: The existence of maternal malignancy may cause false-positive results or failed tests of NIPT. Though recent studies have shown multiple chromosomal aneuploidies (MCA) are associated with malignancy, there is still no effective solution to identify maternal cancer patients from pregnant women with MCA results using NIPT. We aimed to develop a new method to effectively detect maternal cancer in pregnant women with MCA results using NIPT and a random forest classifier to identify the tissue origin of common maternal cancer types. Methods: For examination, 496 participants with MCA results via NIPT were enrolled from January 2016 to June 2019 at BGI. Cancer and non-cancer participants were confirmed through the clinical follow-up. The cohort comprising 42 maternal cancer cases and 294 non-cancer cases enrolled from January 2016 to December 2017 was utilized to develop a method named mean of the top five chromosome z scores (MTOP5Zscores). The remaining 160 participants enrolled from January 2018 to June 2019 were used to validate the performance of MTOP5Zscores. We established a random forest model to classify three common cancer types using normalized Pearson correlation coefficient (NPCC) values, z scores of 22 chromosomes, and seven plasma tumor markers (PTMs) as predictor variables. Results: 62 maternal cancer cases were confirmed with breast cancer, liver cancer, and lymphoma, the most common cancer types. MTOP5Zscores showed a sensitivity of 85% (95% confidence interval (CI), 62.11–96.79%) and specificity of 80% (95% CI, 72.41–88.28%) in the detection of maternal cancer among pregnant women with MCA results. The sensitivity of the classifier was 93.33, 66.67, and 50%, while specificity was 66.67, 90, and 97.06%, and positive predictive value (PPV) was 60.87, 72.73, and 80% for the prediction of breast cancer, liver cancer, and lymphoma, respectively. Conclusion: This study presents a solution to identify maternal cancer patients from pregnant women with MCA results using NIPT, indicating it as a value-added application of NIPT in the detection of maternal malignancies in addition to screening for fetal aneuploidies with no extra cost.
Highlights
Noninvasive prenatal testing (NIPT) first became commercially available to screen for fetal trisomy-21 in 2011 and went global with a rapid speed (Agarwal et al, 2013)
Overview of Maternal Cancer Cases Identified in 496 Participants
A total of 496 participants with multiple chromosomal aneuploidies (MCA) results via NIPT were successfully interviewed in this study, and 62 maternal cancers were confirmed, giving a positive predictive value (PPV) of 12.5% for MCA. It demonstrates that MCA results alone showed unsatisfactory performance for cancer identification; we developed a new method named the mean of the top five chromosome z scores (MTOP5Zscores) to identify maternal cancer cases in pregnant women with MCA results
Summary
Noninvasive prenatal testing (NIPT) first became commercially available to screen for fetal trisomy-21 in 2011 and went global with a rapid speed (Agarwal et al, 2013). In 2017, Dharajiya reported 18 malignant maternal malignancies in 43 non-reportable NIPT cases with altered genomic profiles (Dharajiya et al, 2018) These studies suggest that aneuploidies involving multiple chromosomes are associated with the development of maternal cancer. Though recent studies have shown multiple chromosomal aneuploidies (MCA) are associated with malignancy, there is still no effective solution to identify maternal cancer patients from pregnant women with MCA results using NIPT. We aimed to develop a new method to effectively detect maternal cancer in pregnant women with MCA results using NIPT and a random forest classifier to identify the tissue origin of common maternal cancer types
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