title: Abnormal plasma DNA profiles in early ovarian cancer using a non-invasive prenatal testing platform: implications for cancer screening.
abstract: Non-invasive prenatal testing (NIPT) identifies fetal aneuploidy by sequencing cell-free DNA in the maternal plasma. Pre-symptomatic maternal malignancies have been incidentally detected during NIPT based on abnormal genomic profiles. This low coverage sequencing approach could have potential for ovarian cancer screening in the non-pregnant population. Our objective was to investigate whether plasma DNA sequencing with a clinical whole genome NIPT platform can detect early- and late-stage high-grade serous ovarian carcinomas (HGSOC).
  
  
  
  This is a case control study of prospectively-collected biobank samples comprising preoperative plasma from 32 women with HGSOC (16 'early cancer' (FIGO I-II) and 16 'advanced cancer' (FIGO III-IV)) and 32 benign controls. Plasma DNA from cases and controls were sequenced using a commercial NIPT platform and chromosome dosage measured. Sequencing data were blindly analyzed with two methods: (1) Subchromosomal changes were called using an open source algorithm WISECONDOR (WIthin-SamplE COpy Number aberration DetectOR). Genomic gains or losses ≥ 15 Mb were prespecified as "screen positive" calls, and mapped to recurrent copy number variations reported in an ovarian cancer genome atlas. (2) Selected whole chromosome gains or losses were reported using the routine NIPT pipeline for fetal aneuploidy.
  
  
  
  We detected 13/32 cancer cases using the subchromosomal analysis (sensitivity 40.6 %, 95 % CI, 23.7-59.4 %), including 6/16 early and 7/16 advanced HGSOC cases. Two of 32 benign controls had subchromosomal gains ≥ 15 Mb (specificity 93.8 %, 95 % CI, 79.2-99.2 %). Twelve of the 13 true positive cancer cases exhibited specific recurrent changes reported in HGSOC tumors. The NIPT pipeline resulted in one "monosomy 18" call from the cancer group, and two "monosomy X" calls in the controls.
  
  
  
  Low coverage plasma DNA sequencing used for prenatal testing detected 40.6 % of all HGSOC, including 38 % of early stage cases. Our findings demonstrate the potential of a high throughput sequencing platform to screen for early HGSOC in plasma based on characteristic multiple segmental chromosome gains and losses. The performance of this approach may be further improved by refining bioinformatics algorithms and targeting selected cancer copy number variations.
authors: St John of God Hospital Bendat Family Comprehensive Cancer Centre, Subiaco, Perth, Western Australia, Australia. paul.cohen@sjog.org.au.|School of Women's and Infants' Health, University of Western Australia, Subiaco, Perth, Western Australia, Australia. paul.cohen@sjog.org.au.|Institute for Health Research, University of Notre Dame Australia, Fremantle, Western Australia, Australia. paul.cohen@sjog.org.au.
authors: Paul A
authors: PA
authors: Cohen
authors: Victorian Clinical Genetics Services, Parkville, Victoria, Australia.
authors: Nicola
authors: N
authors: Flowers
authors: Translational Obstetrics Group, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.|Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.
authors: Stephen
authors: S
authors: Tong
authors: Translational Obstetrics Group, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.|Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.
authors: Natalie
authors: N
authors: Hannan
authors: Victorian Clinical Genetics Services, Parkville, Victoria, Australia.|Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia.
authors: Mark D
authors: MD
authors: Pertile
authors: Department of Perinatal Medicine, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.|Translational Obstetrics Group, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.|Department of Obstetrics and Gynaecology, University of Melbourne, Parkville, Victoria, Australia.|Murdoch Children's Research Institute, Parkville, Victoria, Australia.
authors: Lisa
authors: L
authors: Hui
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002869:Chromosome Aberrations; D020732:Cytogenetic Analysis / Q000379:methods; D004247:DNA / Q000097:blood; D056915:DNA Copy Number Variations; D055088:Early Detection of Cancer / Q000379:methods*; D005260:Female; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D008875:Middle Aged; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000473:pathology; D011247:Pregnancy; D011296:Prenatal Diagnosis / Q000379:methods; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
chemical_list: D004247:DNA
keywords: Circulating tumor DNA; Copy number variations; Genomic profiling; High-grade serous carcinoma; Liquid biopsy; Low coverage sequencing; Non-invasive prenatal testing; Ovarian cancer screening