Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer.
Loss of BRCA1 promotor hypermethylation in recurrent high-grade ovarian cancer.
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DOI：
10.18632/oncotarget.20945
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发表时间：
2017-10-10
期刊：
影响因子：
--
通讯作者：
Woelber L
中科院分区：
文献类型：
--
作者：
Prieske K;Prieske S;Joosse SA;Trillsch F;Grimm D;Burandt E;Mahner S;Schmalfeldt B;Milde-Langosch K;Oliveira-Ferrer L;Woelber L
大约20-25%的卵巢癌可归因于生殖系或体细胞BRCA 1/2突变，导致同源重组途径的缺陷。这些基因的失活也可以由表观遗传变化介导，例如，启动子区域中CpG岛的高甲基化。在这种同源重组缺陷型肿瘤中，基于铂的化疗通常是有效的，然而，超甲基化的丧失可能导致难治性疾病。本研究的目的是评估BRCA 1基因启动子高甲基化在铂类化疗后复发性疾病中的稳定性。收集了76例原发性和48例铂敏感性复发性高级别卵巢癌患者的肿瘤组织。在一个12例患者的亚组中，可获得来自初次手术和复发手术的“配对”肿瘤组织。采用甲基化特异性聚合酶链反应评估BRCA 1启动子甲基化状态，并通过桑格测序进行验证。73.7%（56/76）的原发肿瘤和20.8%（10/48）的复发肿瘤存在BRCA 1基因启动子高甲基化。BRCA 1启动子甲基化状态与无进展生存期或总生存期无关。在配对亚组中，83.3%（10/12）的原发肿瘤和16.7%（2/12）的复发肿瘤显示高甲基化。在8例患者中观察到BRCA 1高甲基化丢失，而2例患者具有稳定的甲基化状态。BRCA 1启动子甲基化缺失可能是复发性疾病中恢复BRCA 1功能的机制。但目前其临床意义尚不明确，需进行前瞻性临床试验评价。
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. 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. 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. 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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BRCA1表观遗传失活预测了乳腺癌和卵巢癌中基于铂的化学疗法的敏感性。
影响因子：
3.7
作者：
Stefansson OA;Villanueva A;Vidal A;Martí L;Esteller M
通讯作者：
Esteller M
影响因子：
4.7
作者：
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通讯作者：
Futscher, BW
影响因子：
37.3
作者：
Swisher, Elizabeth M.;Gonzalez, Rachel M.;Welcsh, Piri
通讯作者：
Welcsh, Piri
DOI：
10.1007/s00432-014-1704-5
发表时间：
2014-09-01
影响因子：
3.6
作者：
Ignatov, T.;Eggemann, H.;Ignatov, A.
通讯作者：
Ignatov, A.
影响因子：
64.8
作者：
Patch, Ann-Marie;Christie, Elizabeth L.;Bowtell, David D. L.
通讯作者：
Bowtell, David D. L.