<i>BRCA1</i>epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer

Stefansson, Olafur A.; Villanueva, Alberto; Vidal, August; Martí, Lola; Esteller, Manel

doi:10.4161/epi.22561

Cited by 116 publications

(84 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A representative example is shown in Figure 1B. The MS-PCR product contained 9 CpG sites including the major transcription start site at 1581bp [10][11][12]. All hypermethylated cases (n=66) were highly methylated at all 9 CpG sites, confirming the results of MS-PCR.…”

Section: Brca1 Promoter Hypermethylation Analysis On Primary and Recusupporting

confidence: 68%

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: Brca1 Promoter Hypermethylation Analysis On Primary and Recusupporting

confidence: 68%

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

“…Whatever in vivo or vitro, the point that BRCA1 epigenetic inactivation can predict the sensitivity to platinum-based drugs in breast cancer has been proven. 5,34 In conclusion, lower BRCA1 mRNA expression is significantly associated with better response in patients treated with platinum-based chemotherapy. However, loss of 53BP1 can allow cancer cells to tolerate BRCA1 deficiency and partly restore HR repair deficiency in breast cancer, potentially contributing to platinum resistance.…”

Section: Brca Expressionmentioning

confidence: 89%

Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

Jin

Zhang

et al. 2017

Cancer Biology & Therapy

View full text Add to dashboard Cite

Treatment of triple negative breast cancer (TNBC) has been a big challenge since it is defined. To date, platinum-based chemotherapy has played a significant role in the treatment of TNBC patients. However, some patients do not respond to platinum salts or gradually develop chemoresistance, resulting in little effect, or even some adverse effects. Here, we review numerous preclinical and clinical investigations to summarize possible mechanisms and potential predictive biomarkers of platinum in TNBC. The homologous recombination deficiency (HRD) resulting from the loss of BRCA function is the main rationale of platinum efficacy in TNBC. BRCA mutation and methylation have been demonstrated to be important potential biomarkers. Based on genome-wide effects, BRCA-like classifier can identify the functional loss of BRCA and work as the predictor. HRD score that is able to identify the "BRCAness" and predict the sensitivity of platinum is increasingly considered. Taken together, all findings suggest that HR deficiency profile encompassed by BRCA mutation and high HRD score could predict response to platinum, even to other DNA-damage inducing agents. p53 family members and molecular subtypes of TNBC are also important alternative considerations for predicting platinum response based on the preclinical trials. Currently, tumor infiltrating lymphocyte level and thrombocytopenia are emerging as predictive biomarkers.

show abstract

“…A number of studies have documented aberrant methylation events in breast carcinogenesis and identified specific DNA methylation biomarkers that have significant diagnostic and prognostic potential [9][10][11][12] . Several studies have also identified DNA methylation signatures that can distinguish between breast cancer subtypes [13][14][15][16] , and others that may be predictive of treatment response [17][18][19] .…”

mentioning

confidence: 99%

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

et al. 2015

View full text Add to dashboard Cite

Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.

show abstract

BRCA1epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer

Cited by 116 publications

References 29 publications

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

Loss of BRCA1 promotor hypermethylation in recurrent high grade ovarian cancer

Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

Contact Info

Product

Resources

About