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. 2017 May 1;23(9):2223-2231.
doi: 10.1158/1078-0432.CCR-16-1078. Epub 2016 Nov 14.

Chromosomal Instability in Cell-Free DNA as a Highly Specific Biomarker for Detection of Ovarian Cancer in Women with Adnexal Masses

Adriaan Vanderstichele  1   2 , Pieter Busschaert  1   2 , Dominiek Smeets  3   4 , Chiara Landolfo  1 , Els Van Nieuwenhuysen  1   2 , Karin Leunen  1   2 , Patrick Neven  1   2 , Frédéric Amant  1   2   5 , Sven Mahner  6   7 , Elena Ioana Braicu  8 , Robert Zeilinger  9 , An Coosemans  1   2 , Dirk Timmerman  1 , Diether Lambrechts  10   4 , Ignace Vergote  1   2
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Chromosomal Instability in Cell-Free DNA as a Highly Specific Biomarker for Detection of Ovarian Cancer in Women with Adnexal Masses

Adriaan Vanderstichele et al. Clin Cancer Res. .

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. Clin Cancer Res; 23(9); 2223-31. ©2016 AACR.

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