Prognostic Significance of SLFN11 Methylation in Plasma Cell-Free DNA in Advanced High-Grade Serous Ovarian Cancer

Abstract

Background: Epigenetic alterations in ctDNA are highly promising as a source of novel potential liquid biopsy biomarkers and comprise a very promising liquid biopsy approach in ovarian cancer, for early diagnosis, prognosis and response to treatment. Methods: In the present study, we examined the methylation status of six gene promoters (BRCA1, CST6, MGMT, RASSF10, SLFN11 and USP44) in high-grade serous ovarian cancer (HGSOC). We evaluated the prognostic significance of DNA methylation of these six gene promoters in primary tumors (FFPEs) and plasma cfDNA samples from patients with early, advanced and metastatic HGSOC. Results: We report for the first time that the DNA methylation of SLFN11 in plasma cfDNA was significantly correlated with worse PFS (p = 0.045) in advanced stage HGSOC. Conclusions: Our results strongly indicate that SLFN11 epigenetic inactivation could be a predictor of resistance to platinum drugs in ovarian cancer. Our results should be further validated in studies based on a larger cohort of patients, in order to further explore whether the DNA methylation of SLFN11 promoter could serve as a potential prognostic DNA methylation biomarker and a predictor of resistance to platinum-based chemotherapy in ovarian cancer.

Early diagnosis of ovarian cancer based on methylation profiles in peripheral blood cell-free DNA: a systematic review

“…3500× g , 1 min, 4 °C 2. 3500× g , 1 min, 4 °C Stored at − 80 °C MagMax Cell-Free DNA Isolation Kit (ThermoFisher Scientific) Premium Bisulfite Kit (Diagenode) Modified DNA stored at − 20 °C until analysis Tserpeli [ 43 ] Plasma 2 N/A EDTA 1500× g , 10 min Stored at − 80 °C QIAamp Circulating Nucleic Acid Kit (QIAGEN) EZ DNA Methylation Gold Kit (Zymo Research) Modified DNA stored at − 70 °C until analysis Marinelli [ 44 ] Plasma 3–6 Retrospective EDTA LBgard® Blood Tubes (Biomatrica) N/A QIAamp DNA Blood Kit (QIAGEN) EZ-96 DNA Methylation Kit (Zymo Research) Tomeva [ 45 ] Plasma 4 Prospective EDTA Processed within 1 h after blood draw 1. 2000× g , 10 min, 4–8 °C 2.…”

“…BRCA1 was investigated in six studies, but only three studies had available data for evaluating the gene as a single biomarker for OC. The sensitivity was reported to be 12.2% (95% CI 6.01–21.3)/20.8% (95% CI 10.5–35.0), 62.3% (95% CI 47.9–75.2), and 93.9% (95% CI 79.8–99.3), with corresponding specificities of 100% (95% CI 87.2–100), 77.8% (95% CI 57.7–91.4), and 48.5% (95% CI 30.8–66.5), respectively [ 20 , 37 , 43 ]. For BRCA1, the performance varied substantially, and BRCA1 either had a too low sensitivity or a too low specificity to be a single biomarker for OC.…”

Circulating Tumor DNA—A Novel Biomarker of Tumor Progression and Its Favorable Detection Techniques

“…BRCA1, SLFN11, and USP44 methylation markers were screened by real-time quantitative methylation PCR in cancer tissues and peripheral blood of patients with high-grade serous ovarian cancer. The methylation level of SLFN44 in the ctDNA of patients with advanced cancer was significantly correlated with poor progression-free survival [ 106 ]. A meta-analysis [ 107 ] of eight studies involving 672 patients with ovarian cancer showed that ctDNA was associated with the tumor size and stage.…”

Ovarian Cancer Diagnosis and Prognosis Based on Cell-Free DNA Methylation

“…For the first time, Tserpeli et al 67 reported that the methylation status of SLFN11 in cfDNA within plasma was associated with decreased PFS in advanced HGSOC ( P = .045). Liang et al 63 sequenced plasma-derived cfDNA using ELSA-seq from eligible participants.…”