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Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer

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 r...

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Autores principales: Prieske, Katharina, Prieske, Stefan, Joosse, Simon A., Trillsch, Fabian, Grimm, Donata, Burandt, Eike, Mahner, Sven, Schmalfeldt, Barbara, Milde-Langosch, Karin, Oliveira-Ferrer, Leticia, Woelber, Linn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Impact Journals LLC 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669950/
https://www.ncbi.nlm.nih.gov/pubmed/29137324
http://dx.doi.org/10.18632/oncotarget.20945
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author Prieske, Katharina
Prieske, Stefan
Joosse, Simon A.
Trillsch, Fabian
Grimm, Donata
Burandt, Eike
Mahner, Sven
Schmalfeldt, Barbara
Milde-Langosch, Karin
Oliveira-Ferrer, Leticia
Woelber, Linn
author_facet Prieske, Katharina
Prieske, Stefan
Joosse, Simon A.
Trillsch, Fabian
Grimm, Donata
Burandt, Eike
Mahner, Sven
Schmalfeldt, Barbara
Milde-Langosch, Karin
Oliveira-Ferrer, Leticia
Woelber, Linn
author_sort Prieske, Katharina
collection PubMed
description 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.
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spelling pubmed-56699502017-11-09 Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer Prieske, Katharina Prieske, Stefan Joosse, Simon A. Trillsch, Fabian Grimm, Donata Burandt, Eike Mahner, Sven Schmalfeldt, Barbara Milde-Langosch, Karin Oliveira-Ferrer, Leticia Woelber, Linn Oncotarget Research Paper 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. Impact Journals LLC 2017-09-15 /pmc/articles/PMC5669950/ /pubmed/29137324 http://dx.doi.org/10.18632/oncotarget.20945 Text en Copyright: © 2017 Prieske et al. http://creativecommons.org/licenses/by/3.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/) 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Paper
Prieske, Katharina
Prieske, Stefan
Joosse, Simon A.
Trillsch, Fabian
Grimm, Donata
Burandt, Eike
Mahner, Sven
Schmalfeldt, Barbara
Milde-Langosch, Karin
Oliveira-Ferrer, Leticia
Woelber, Linn
Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
title Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
title_full Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
title_fullStr Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
title_full_unstemmed Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
title_short Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer
title_sort loss of brca1 promotor hypermethylation in recurrent high-grade ovarian cancer
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669950/
https://www.ncbi.nlm.nih.gov/pubmed/29137324
http://dx.doi.org/10.18632/oncotarget.20945
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