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The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer

Widschwendter, M; Zikan, M; Wahl, B; Lempiainen, H; Paprotka, T; Evans, I; Jones, A; ... Wittenberger, T; + view all (2017) The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer. Genome Medicine , 9 , Article 116. 10.1186/s13073-017-0500-7. Green open access

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Abstract

Background: Despite a myriad of attempts in the last three decades to diagnose ovarian cancer (OC) earlier, this clinical aim still remains a significant challenge. Aberrant methylation patterns of linked CpGs analyzed in DNA fragments shed by cancers into the bloodstream (i.e. cell-free DNA) can provide highly specific signals indicating cancer presence. Methods: We analyzed 699 cancerous and non-cancerous tissues using a methylation array or reduced representation bisulfite sequencing to discover the most specific OC methylation patterns. A three-DNA-methylation-serum-marker panel was developed using targeted ultra-high coverage bisulfite sequencing in 151 women and validated in 250 women with various conditions, particularly in those associated with high CA125 levels (endometriosis and other benign pelvic masses), serial samples from 25 patients undergoing neoadjuvant chemotherapy, and a nested case control study of 172 UKCTOCS control arm participants which included serum samples up to two years before OC diagnosis. Results: The cell-free DNA amount and average fragment size in the serum samples was up to ten times higher than average published values (based on samples that were immediately processed) due to leakage of DNA from white blood cells owing to delayed time to serum separation. Despite this, the marker panel discriminated high grade serous OC patients from healthy women or patients with a benign pelvic mass with specificity/sensitivity of 90.7% (95% confidence interval [CI] = 84.3–94.8%) and 41.4% (95% CI = 24.1–60.9%), respectively. Levels of all three markers plummeted after exposure to chemotherapy and correctly identified 78% and 86% responders and non-responders (Fisher’s exact test, p = 0.04), respectively, which was superior to a CA125 cut-off of 35 IU/mL (20% and 75%). 57.9% (95% CI 34.0–78.9%) of women who developed OC within two years of sample collection were identified with a specificity of 88.1% (95% CI = 77.3–94.3%). Sensitivity and specificity improved further when specifically analyzing CA125 negative samples only (63.6% and 87.5%, respectively). Conclusions: Our data suggest that DNA methylation patterns in cell-free DNA have the potential to detect a proportion of OCs up to two years in advance of diagnosis and may potentially guide personalized treatment. The prospective use of novel collection vials, which stabilize blood cells and reduce background DNA contamination in serum/plasma samples, will facilitate clinical implementation of liquid biopsy analyses.

Type: Article
Title: The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer
Open access status: An open access version is available from UCL Discovery
DOI: 10.1186/s13073-017-0500-7
Publisher version: http://doi.org/10.1186/s13073-017-0500-7
Language: English
Additional information: Copyright © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Keywords: Cell-free DNA, DNA methylation, Serum DNA, Ovarian cancer, Early diagnosis, Screening, Personalized treatment
URI: http://discovery.ucl.ac.uk/id/eprint/10041287
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