Journal
MOLECULAR ONCOLOGY
Volume 15, Issue 12, Pages 3615-3625Publisher
WILEY
DOI: 10.1002/1878-0261.13108
Keywords
BRCA1; ctDNA; liquid biopsy; MS-qPCR
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Funding
- Erich und Gertrud Roggenbuck Foundation
- Projekt DEAL
- Hamburg Act for the Promotion of Young Researchers and Artists, University of Hamburg
- Mildred Scheel Cancer Career Center HaTriCS4
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The study found that BRCA1 promoter hypermethylation is frequently observed in ovarian cancer patients and often reversed upon recurrence, indicating the selection of therapy-resistant clones and unfavorable clinical outcomes.
Methylation of the BRCA1 promoter is an epigenetic gene expression regulator and is frequently observed in ovarian cancer; however, conversion of methylation status is thought to drive disease recurrence. Therefore, longitudinal monitoring of methylation status by liquid biopsy in cell-free DNA may be a predictive marker. In total, 135 plasma samples were collected from 69 ovarian cancer patients before and during systemic treatment. Our liquid biopsy assay could detect down to a single molecule of methylated DNA in a high background of normal DNA (0.03%) with perfect specificity in control samples. We found that 60% of the cancer patients exhibited BRCA1 promoter hypermethylation at one point, although 24% lost hypermethylation during treatment. Multivariate survival analyses indicate that relapses are independent events and that hypermethylation and methylation conversion are independently correlated to longer relapse-free survival. We present a highly sensitive and specific methylation-specific quantitative PCR-based liquid biopsy assay. BRCA1 promoter hypermethylation is frequently found in ovarian cancer and is often reversed upon recurrence, indicating the selection of therapy-resistant clones and unfavorable clinical outcome.
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