title: Chromosomal Instability in Cell-Free DNA as a Highly Specific Biomarker for Detection of Ovarian Cancer in Women with Adnexal Masses.
abstract: Purpose:Chromosomal instability is a hallmark of ovarian cancer. Here, we explore copy-number alteration (CNA) profiling in cell-free DNA as a potential biomarker to detect malignancy in patients presenting with an adnexal mass.Experimental Design:We prospectively enrolled 68 patients with an adnexal mass, of which 57 were diagnosed with invasive or borderline carcinoma and 11 with benign disease. Cell-free DNA was extracted from plasma and analyzed by low-coverage whole-genome sequencing.Results:Patterns of chromosomal instability were detectable in cell-free DNA using 44 healthy individuals as a reference. Profiles were representative of those observed in matching tumor tissue and contained CNAs enriched in two large datasets of high-grade serous ovarian cancer (HGSOC). Quantitative measures of chromosomal instability, referred to as genome-widez-scores, were significantly higher in patients with ovarian carcinoma than in healthy individuals or patients with benign disease. Cell-free DNA testing improved malignancy detection (AUC 0.89) over serum CA-125 (AUC 0.78) or the risk of malignancy index (RMI, AUC 0.81). AUC values of cell-free DNA testing even further increased for HGSOC patients specifically (AUC 0.94). At a specificity of 99.6%, a theoretical threshold required for ovarian cancer screening, sensitivity of cell-free DNA testing was 2- to 5-fold higher compared with CA-125 and RMI testing.Conclusions:This is the first study evaluating the potential of cell-free DNA for the diagnosis of primary ovarian cancer using chromosomal instability as a read-out. We present a promising method to increase specificity of presurgical prediction of malignancy in patients with adnexal masses.Clin Cancer Res; 23(9); 2223-31. ©2016 AACR.
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Adriaan
authors.initials: A
authors.lastname: Vanderstichele
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Busschaert
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Dominiek
authors.initials: D
authors.lastname: Smeets
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Chiara
authors.initials: C
authors.lastname: Landolfo
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Els
authors.initials: E
authors.lastname: Van Nieuwenhuysen
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Leunen
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.|Center for Gynecologic Oncology Amsterdam (CGOA), Netherlands Cancer Institute (NKI), Amsterdam, the Netherlands.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
authors.affiliation: Department of Gynecology and Gynecologic Oncology, Hamburg-Eppendorf University Medical Center, University Cancer Center Hamburg-Eppendorf (UCCH), Hamburg, Germany.|Department of Gynecology and Obstetrics, University of Munich - LMU, Munich, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Mahner
authors.affiliation: Department of Gynecology, Campus Virchow-Klinikum, Charité University Hospital, European Competence Center for Ovarian Cancer, Berlin, Germany.
authors.forename: Elena Ioana
authors.initials: EI
authors.lastname: Braicu
authors.affiliation: Department of Obstetrics and Gynecology, Molecular Oncology Group, Comprehensive Cancer Center, Gynecologic Cancer Unit, Medical University of Vienna, Vienna, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeilinger
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Coosemans
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.
authors.forename: Dirk
authors.initials: D
authors.lastname: Timmerman
authors.affiliation: Vesalius Research Center, VIB, Leuven, Belgium. diether.lambrechts@vib-kuleuven.be.|Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Department of Gynaecology and Obstetrics, University Hospitals Leuven, Leuven, Belgium.|Division of Gynaecological Oncology, Leuven Cancer Institute, KU Leuven, Leuven, Belgium.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
mesh_terms: D000291:Adnexal Diseases / Q000097:blood* / Q000150:complications / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000097:blood*; D018394:CA-125 Antigen / Q000097:blood; D000073888:Cell-Free Nucleic Acids / Q000097:blood; D043171:Chromosomal Instability / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000097:blood* / Q000150:complications / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D000073888:Cell-Free Nucleic Acids