The potential of circulating tumor DNA methylation analysis for the early detection and management of ovarian cancer
Martin Widschwendter,Michal Zikan,Benjamin Wahl,Harri Lempiäinen,Tobias Paprotka,Iona Evans,Allison Jones,Shohreh Ghazali,Daniel Reisel,Johannes Eichner,Tamas Rujan,Zhen Yang,Andrew E. Teschendorff,Andrew E. Teschendorff,Andy Ryan,David Cibula,Usha Menon,Timo Wittenberger +17 more
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TLDR
The 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.Abstract:
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. 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. 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). 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.read more
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Epithelial Ovarian Cancer
TL;DR: Urgent progress is needed to develop evidence and consensus-based treatment guidelines for each subgroup, and requires close international cooperation in conducting clinical trials through academic research groups such as the Gynecologic Cancer Intergroup.
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Unravelling tumour heterogeneity by single-cell profiling of circulating tumour cells
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Xingdong Chen,Jeffrey A. Gole,Athurva Gore,He Qiye,Ming Lu,Ming Lu,Jun Min,Ziyu Yuan,Xiaorong Yang,Xiaorong Yang,Yanfeng Jiang,Tiejun Zhang,Chen Suo,Xiaojie Li,Lei Cheng,Zhenhua Zhang,Hongyu Niu,Zhe Li,Zhen Xie,Han Shi,Xiang Zhang,Min Fan,Xiaofeng Wang,Yajun Yang,Justin Dang,Catie McConnell,Juan Zhang,Jiucun Wang,Shun-Zhang Yu,Weimin Ye,Weimin Ye,Yuan Gao,Kun Zhang,Rui Liu,Li Jin +34 more
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A radioimmunoassay using a monoclonal antibody to monitor the course of epithelial ovarian cancer.
Robert C. Bast,Thomas L. Klug,E St John,Eric Jenison,Jonathan M. Niloff,Herbert Lazarus,Ross S. Berkowitz,T. Leavitt,C.T. Griffiths,Leroy M. Parker,Vincent R. Zurawski,Robert C. Knapp +11 more
TL;DR: Determination of CA 125 levels may aid in monitoring the response to treatment in patients with epithelial ovarian cancer, and rising or falling levels ofCA 125 correlated with progression or regression of disease in 42 of 45 instances.
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