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

Abstract

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. 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. 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 -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. 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. .

Differences in ultrasound features of papillations in unilocular‐solid adnexal cysts: a retrospective international multicenter study

“…Unfortunately, however, we found that the three entities cannot be distinguished by using the ultrasound features that we investigated in this study. It would be of interest to investigate if novel biomarkers can be used to indicate malignancy in unilocular‐solid cysts with papillations but no other solid components.…”

Validation of the Performance of International Ovarian Tumor Analysis (IOTA) Methods in the Diagnosis of Early Stage Ovarian Cancer in a Non-Screening Population

“…To allow detection of this aggressive type of ovarian cancer, there is ongoing search for sensitive biomarkers expressed early in ovarian carcinogenesis. More recently, there is increasing interest in the use of genomic profiling as a potential candidate for the detection of ovarian malignancies [50,51]. Further research should explore whether IOTA methods may serve as a second stage test in a program of ovarian cancer screening to avoid unnecessary surgery without delaying a diagnosis of ovarian cancer.…”

Liquid biopsy in ovarian cancer: recent advances on circulating tumor cells and circulating tumor DNA

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