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Vanderstichele, Adriaan; Busschaert, Pieter; Smeets, Dominiek; Landolfo, Chiara; Nieuwenhuysen, Els van; Leunen, Karin; Neven, Patrick; Amant, Frederic; Mahner, Sven; Braicu, Elena Ioana; Zeilinger, Robert; Coosemans, An; Timmerman, Dirk; Lambrechts, Diether; Vergote, Ignace (2017): Chromosomal Instability in Cell-Free DNA as a Highly Specific Biomarker for Detection of Ovarian Cancer in Women with Adnexal Masses. In: Clinical Cancer Research, Vol. 23, No. 9: pp. 2223-2231
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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-wide z-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. (C) 2016 AACR.