Diana W Bianchi1, Darya Chudova2, Amy J Sehnert2, Sucheta Bhatt2, Kathryn Murray3, Tracy L Prosen4, Judy E Garber5, Louise Wilkins-Haug6, Neeta L Vora7, Stephen Warsof8, James Goldberg9, Tina Ziainia10, Meredith Halks-Miller2. 1. Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts. 2. Illumina, Redwood City, California. 3. Center for Genetics and Maternal Fetal Medicine, Springfield, Oregon. 4. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis. 5. Dana-Farber Cancer Institute, Boston, Massachusetts. 6. Division of Maternal Fetal Medicine and Reproductive Genetics, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts. 7. University of North Carolina, Chapel Hill. 8. Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk. 9. San Francisco Perinatal Associates, San Francisco, California. 10. Sharp Rees-Stealy Medical Group, San Diego, California.
Abstract
IMPORTANCE: 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 MEASURES: Detailed 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 RELEVANCE: In 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.
IMPORTANCE: 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 MEASURES: Detailed 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 RELEVANCE: In 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.
Authors: Marija Debeljak; Michael Noë; Stacy L Riel; Lisa M Haley; Alexis L Norris; Derek A Anderson; Emily M Adams; Masaya Suenaga; Katie F Beierl; Ming-Tseh Lin; Michael G Goggins; Christopher D Gocke; James R Eshleman Journal: Mol Diagn Ther Date: 2018-10 Impact factor: 4.074
Authors: Matthew R Grace; Emily Hardisty; Sarah K Dotters-Katz; Neeta L Vora; Jeffrey A Kuller Journal: Obstet Gynecol Surv Date: 2016-08 Impact factor: 2.347