BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer. Issue 12 (12th October 2021)

• Record Type: Journal Article
• Authors: Elazezy, Maha; Prieske, Katharina; Kluwe, Lan; Oliveira‐Ferrer, Leticia; Peine, Sven; Müller, Volkmar; Woelber, Linn; Schmalfeldt, Barbara; Pantel, Klaus; Joosse, Simon A.
• Is Part Of: Molecular oncology. Volume 15:Issue 12(2021)
• Page Start: 3615
• Page End: 3625
• Publication Date: 2021-10-12
• Subjects: BRCA1 -- ctDNA -- liquid biopsy -- MS‐qPCR; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.13108
• Languages: English
• ISSNs: 1574-7891

Abstract

Abstract : 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. Abstract : In patients with ovarian cancer (OC) undergoing platinum‐based chemotherapy and PARP‐inhibitor treatment, BRCA1 deficiency is used as major predictive marker for estimating response to therapy. Here, we present a highly sensitive and specific liquid biopsy assay that assesses BRCA1 gene promoter hypermethylation on circulating tumor DNA (ctDNA) isolated from blood plasma. Our results suggest that hypermethylation and methylation conversion of the BRCA1 promoter in ctDNA are independently correlated to longer progression‐free survival of patients with OC.