<i>BRCA1</i> promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer

Elazezy, Maha; Oliveira‐Ferrer, Leticia; Peine, Sven; Müller, Volkmar; Woelber, Linn; Schmalfeldt, Barbara; Pantel, Klaus; Joosse, Simon A.

doi:10.1002/1878-0261.13108

Cited by 11 publications

(4 citation statements)

References 32 publications

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“… 17 , 18 However, epigenetic changes may be more easily reversed than genetic mutations; a recent analysis found that 24% of ovarian tumors lost BRCA1 hypermethylation during treatment. 19 Therefore, it is possible that hypermethylation may account for a meaningful proportion of tumors with high genomic instability and that these tumors are sensitive to PARP inhibition in the first-line setting; however, reversion of hypermethylation with treatment may lead to PARP inhibitor resistance in subsequent lines of therapy.…”

Section: Discussionmentioning

confidence: 99%

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial

Pujade-Lauraine

Brown

Barnicle

et al. 2023

JCO Precision Oncology

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PURPOSE The PAOLA-1/ENGOT-ov25 trial of maintenance olaparib plus bevacizumab for newly diagnosed advanced high-grade ovarian cancer demonstrated a significant progression-free survival (PFS) benefit over placebo plus bevacizumab, particularly in patients with homologous recombination deficiency (HRD)–positive tumors. We explored whether mutations in non- BRCA1 or BRCA2 homologous recombination repair (non–BRCA HRRm) genes predicted benefit from olaparib plus bevacizumab in PAOLA-1. METHODS Eight hundred and six patients were randomly assigned (2:1). Tumors were analyzed using the Myriad MyChoice HRD Plus assay to assess non–BRCA HRRm and HRD status; HRD was based on a genomic instability score (GIS) of ≥ 42. In this exploratory analysis, PFS was assessed in patients harboring deleterious mutations using six non–BRCA HRR gene panels, three devised for this analysis and three previously published. RESULTS The non–BRCA HRRm prevalence ranged from 30 of 806 (3.7%) to 79 of 806 (9.8%) depending on the gene panel used, whereas 152 of 806 (18.9%) had non‐ BRCA1 or BRCA2 mutation HRD-positive tumors. The majority of tumors harboring non–BRCA HRRm had a low median GIS; however, a GIS of > 42 was observed for tumors with mutations in five HRR genes ( BLM, BRIP1, RAD51C, PALB2, and RAD51D). Rates of gene-specific biallelic loss were variable (0% to 100%) in non–BRCA HRRm tumors relative to BRCA1-mutated (99%) or BRCA2-mutated (86%) tumors. Across all gene panels tested, hazard ratios for PFS (95% CI) ranged from 0.92 (0.51 to 1.73) to 1.83 (0.76 to 5.43). CONCLUSION Acknowledging limitations of small subgroup sizes, non–BRCA HRRm gene panels were not predictive of PFS benefit with maintenance olaparib plus bevacizumab versus placebo plus bevacizumab in PAOLA-1, irrespective of the gene panel tested. Current gene panels exploring HRRm should not be considered a substitute for HRD determined by BRCA mutation status and genomic instability testing in first-line high-grade ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial

Pujade-Lauraine

Brown

Barnicle

et al. 2023

JCO Precision Oncology

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“…This finding is in agreement with a previous study which showed that patients with ovarian and non-small cell lung cancer carrying SLFN11 hypermethylation in primary tumors had a poor response to both cisplatin and carboplatin treatments [ 45 ]. According to the literature, variable levels of BRCA1 promoter methylation in ovarian cancer have been previously reported, ranging from 5–90% [ 51 , 52 , 53 ]. In another study, Wang et al reported that compared to stage I and healthy subjects, there were higher BRCA1 promoter methylation frequencies in stage II and III ovarian cancers [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

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

Tserpeli

Stergiopoulou

Londra

et al. 2021

Cancers

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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.

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“… 180 CtDNA methylation in liquid biopsies can be analysed as either a single region (e.g. a single gene promoter), 181 – 184 as a panel of loci (e.g. multiple gene promoters) 185 – 189 or using genome-wide epigenetic signatures.…”

Section: Tumour Suppressor Methylation In Liquid Biopsiesmentioning

confidence: 99%

The role of aberrant DNA methylation in cancer initiation and clinical impacts

Geissler,

Nesic,

Kondrashova

et al. 2024

Ther Adv Med Oncol

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Epigenetic alterations, including aberrant DNA methylation, are now recognized as bone fide hallmarks of cancer, which can contribute to cancer initiation, progression, therapy responses and therapy resistance. Methylation of gene promoters can have a range of impacts on cancer risk, clinical stratification and therapeutic outcomes. We provide several important examples of genes, which can be silenced or activated by promoter methylation and highlight their clinical implications. These include the mismatch DNA repair genes MLH1 and MSH2, homologous recombination DNA repair genes BRCA1 and RAD51C, the TERT oncogene and genes within the P15/P16/RB1/E2F tumour suppressor axis. We also discuss how these methylation changes might occur in the first place – whether in the context of the CpG island methylator phenotype or constitutional DNA methylation. The choice of assay used to measure methylation can have a significant impact on interpretation of methylation states, and some examples where this can influence clinical decision-making are presented. Aberrant DNA methylation patterns in circulating tumour DNA (ctDNA) are also showing great promise in the context of non-invasive cancer detection and monitoring using liquid biopsies; however, caution must be taken in interpreting these results in cases where constitutional methylation may be present. Thus, this review aims to provide researchers and clinicians with a comprehensive summary of this broad, but important subject, illustrating the potentials and pitfalls of assessing aberrant DNA methylation in cancer.

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BRCA1 promoter hypermethylation on circulating tumor DNA correlates with improved survival of patients with ovarian cancer

Cited by 11 publications

References 32 publications

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial

Homologous Recombination Repair Gene Mutations to Predict Olaparib Plus Bevacizumab Efficacy in the First-Line Ovarian Cancer PAOLA-1/ENGOT-ov25 Trial

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

The role of aberrant DNA methylation in cancer initiation and clinical impacts

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