BRCA1 gene promoter methylation status in high-grade serous ovarian cancer patients – A study of the tumour Bank ovarian cancer (TOC) and ovarian cancer diagnosis consortium (OVCAD)

Ruscito, Ilary; Dimitrova, Desislava; Vasconcelos, Inês; Gellhaus, Katharina; Schwachula, Tim; Bellati, Filippo; Zeillinger, Robert; Benedetti‐Panici, Pierluigi; Vergote, Ignace; Mahner, Sven; Cacsire-Tong, Dan; Concin, Nicole; Darb‐Esfahani, Silvia; Lambrechts, Sandrina; Sehouli, Jalid; Olek, Sven; Braicu, Elena Ioana

doi:10.1016/j.ejca.2014.05.001

Cited by 82 publications

(71 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Accordingly, in a thorough analysis of 489 high-grade serous ovarian cancer samples, the TCGA did also fail to show an impact on OS for BRCA1 methylated tumors [1]. These results have been confirmed by other groups as well [5,9]. Taken together, these results suggest that hypermethylation is either heterogeneous or a dynamic process in ovarian cancer and may not be a good predictor for platinum-based chemotherapy.…”

Section: Discussionsupporting

confidence: 75%

“…BRCA1 promoter hypermethylation has been described previously in primary high-grade serous ovarian cancer, methylation rates ranging from 10-89% [1,[5][6][7][8]. However, most studies report a methylation rate of 10-35% which is clearly below the 73% methylated cases in our cohort.…”

Section: Discussioncontrasting

confidence: 52%

“…The TCGA reported that epigenetic silencing of BRCA1 is mutually exclusive of BRCA1/2 mutations [1]. As results regarding the impact of BRCA1 silencing by promoter hypermethylation on progression free survival (PFS) or OS vary [1,5,9], the stability and clinical significance of this alteration remains currently unclear. The aim of this study was therefore to investigate the stability of BRCA1 promoter hypermethylation in platinum sensitive recurrent disease after platinum based chemotherapy.…”

Section: Research Papermentioning

confidence: 99%

“…Besides germline and somatic mutations, epigenetic modifications like promoter hypermethylation of BRCA1 can also lead to downregulation of gene expression [3,4] and thus silencing of the BRCA1. Methylation of CpG islands in the BRCA1 promoter of primary high-grade ovarian carcinomas has been described ranging from 11-89% [1,[5][6][7][8]. The TCGA reported that epigenetic silencing of BRCA1 is mutually exclusive of BRCA1/2 mutations [1].…”

Section: Research Papermentioning

confidence: 99%

See 3 more Smart Citations

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

Prieske

Joosse

Trillsch

et al. 2016

Geburtshilfe Frauenheilkd

View full text Add to dashboard Cite

Background: Approximately 20-25% of ovarian cancers are attributable to germline or somatic BRCA1/2 mutations, resulting in defects in the homologous recombination pathway. Inactivation of these genes can also be mediated by epigenetic changes, e.g., hypermethylation of CpG islands in the promoter regions. In such homologous recombination deficient tumors, platinum based chemotherapy is in general effective, however, loss of hypermethylation might lead to refractory disease. The aim of this study was to evaluate the stability of BRCA1 promoter hypermethylation in recurrent disease after platinum based chemotherapy.Methods: Tumor tissue from 76 patients with primary and 48 patients with platinum-sensitive recurrent high-grade ovarian cancer was collected. In a subgroup of 12 patients, 'paired' tumor tissue from primary and recurrent surgery was available. BRCA1 promoter methylation status was assessed using methylation specific polymerase chain reaction and was verified by Sanger Sequencing.Results: 73.7% (56/76) of primary and 20.8% (10/48) of recurrent tumors displayed BRCA1 promoter hypermethylation. BRCA1 promoter methylation status was not associated with progression-free-or overall survival. In the paired subgroup 83.3% (10/12) of the primary vs. 16.7% (2/12) of the recurrent tumors showed hypermethylation. In eight patients loss of BRCA1 hypermethylation was observed, whereas two patients had stable methylation status.Conclusions: Loss of BRCA1 promoter methylation may be a mechanism to restore BRCA1 function in recurrent disease. However, currently the clinical significance is still unclear and should be evaluated in prospective clinical trials.

show abstract

Section: Discussionsupporting

confidence: 75%

Section: Discussioncontrasting

confidence: 52%

Section: Research Papermentioning

confidence: 99%

Section: Research Papermentioning

confidence: 99%

See 2 more Smart Citations

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

Prieske

Joosse

Trillsch

et al. 2016

Geburtshilfe Frauenheilkd

View full text Add to dashboard Cite

show abstract

“…Thus, patients with hypermethylated BRCA1 may benefit from PARPi therapy, although it is possible that they may not demonstrate the same degree of drug sensitivity as patients with germ line BRCA mutations (Cancer Genome Atlas Research Network 2011). This was alluded to in a study by Ruscito and colleagues, who showed that even though 14.8% of HGOSC had hypermethylation in a selected region of the BRCA1 promoter, this had no effect on the PFS or OS rate in patients treated with conventional chemotherapy (Ruscito et al 2014). Methylation status of the BRCA genes may be investigated using a variety of methods including direct bisulfite sequencing, methylationspecific PCR, methylation microarrays, pyrosequencing, and NGS, the choice of which would be dependent on factors such as the type of biological samples and tumor content present (Ibragimova & Cairns 2011).…”

Section: Brca Inactivation In Sporadic Cancersmentioning

confidence: 99%

Evaluation of the methods to identify patients who may benefit from PARP inhibitor use

Lim

Ngeow

2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

The effectiveness of poly (ADP-ribose) polymerase inhibitors (PARPi) in treating cancers associated with BRCA1/2 mutations hinges upon the concept of synthetic lethality and exemplifies the principles of precision medicine. Currently, most clinical trials are recruiting patients based on pathological subtypes or have included BRCA mutation analysis (germ line and/or somatic) as part of the selection criteria. Mounting evidence, however, suggests that these drugs may also be efficacious in tumors with defects in other genes involved in the homologous recombination repair pathway. Advances in molecular profiling techniques together with increased research efforts have led to a better understanding of the molecular aberrations underlying this BRCA-like phenotype and helped broaden the concept of BRCAness. Hence, it is likely that the list of predictive biomarkers for PARPi therapy will increase in future. There is currently no gold standard method of testing for PARPi response and no universal guidelines are in place on how to incorporate biomarker testing into routine clinical diagnostics. In this review, we explore the concept of BRCAness and highlight the different methods that have been used to identify patients who may benefit from the use of these anticancer agents. The identification of predictive biomarkers is crucial in improving patient selection and expanding the clinical applications of PARPi therapy. 23:6 Review D Lim and J NgeowEvaluating BRCAness for PARP inhibitor use

show abstract