Chromosomal instability in cell-free DNA as a highly specific biomarker for ovarian cancer detection

Chromosomal instability in cell-free DNA as a highly specific biomarker for ovarian cancer detectionBackground and Aims: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.Methods:We prospectively enrolled 58 patients with an adnexal mass, of which 47 were diagnosed with invasive or borderline carcinoma and 11 with benign disease. Cell-free DNA was extracted from plasma and analyzed by whole-genome sequencing.Results:Patterns of chromosomal instability were detectable in cell-free DNA using healthy individuals as a reference. These profiles were representative of those observed in matching tumor tissue and were enriched for CNAs recurrently observed in 2 large datasets of high-grade serous ovarian cancer (HGSOC). Quantitative measures of chromosomal instability, genome-wide z-scores, were significantly higher in patients with invasive or borderline carcinoma than in healthy individuals or patients with benign disease. Remarkably, cell-free DNA testing improved malignancy detection (AUC=0.88) over clinically-established methods using serum CA-125 (AUC 0.79) or the risk of malignancy index (RMI, AUC 0.81). AUC values of cell-free DNA even further increased for HGSOC patients alone (AUC 0.94). At a specificity of 99.6%, required for ovarian cancer screening, sensitivity of cell-free DNA testing was 2 to 5-fold higher compared to 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 propose this novel method to detect malignancy with high specificity in patients presenting with an adnexal mass.

Jaar van publicatie:2016