title: Noninvasive Prenatal Testing and Incidental Detection of Occult Maternal Malignancies.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  NIPT for fetal aneuploidy screening (chromosomes 13, 18, 21, X, and Y).
  
  
  METHODS
  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
  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.affiliation: Mother Infant Research Institute, Tufts Medical Center, Boston, Massachusetts.
authors.forename: Diana W
authors.initials: DW
authors.lastname: Bianchi
authors.affiliation: Illumina, Redwood City, California.
authors.forename: Darya
authors.initials: D
authors.lastname: Chudova
authors.affiliation: Illumina, Redwood City, California.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Sehnert
authors.affiliation: Illumina, Redwood City, California.
authors.forename: Sucheta
authors.initials: S
authors.lastname: Bhatt
authors.affiliation: Center for Genetics and Maternal Fetal Medicine, Springfield, Oregon.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Murray
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, University of Minnesota, Minneapolis.
authors.forename: Tracy L
authors.initials: TL
authors.lastname: Prosen
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Judy E
authors.initials: JE
authors.lastname: Garber
authors.affiliation: Division of Maternal Fetal Medicine and Reproductive Genetics, Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Louise
authors.initials: L
authors.lastname: Wilkins-Haug
authors.affiliation: University of North Carolina, Chapel Hill.
authors.forename: Neeta L
authors.initials: NL
authors.lastname: Vora
authors.affiliation: Division of Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Eastern Virginia Medical School, Norfolk.
authors.forename: Stephen
authors.initials: S
authors.lastname: Warsof
authors.affiliation: San Francisco Perinatal Associates, San Francisco, California.
authors.forename: James
authors.initials: J
authors.lastname: Goldberg
authors.affiliation: Sharp Rees-Stealy Medical Group, San Diego, California.
authors.forename: Tina
authors.initials: T
authors.lastname: Ziainia
authors.affiliation: Illumina, Redwood City, California.
authors.forename: Meredith
authors.initials: M
authors.lastname: Halks-Miller
mesh_terms: D000328:Adult; D000782:Aneuploidy; D025063:Chromosome Disorders / Q000175:diagnosis*; D004247:DNA / Q000097:blood*; D005189:False Positive Reactions; D005260:Female; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D033162:Incidental Findings; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics*; D011247:Pregnancy; D011296:Prenatal Diagnosis; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D004247:DNA