Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas
Methylation and protein expression of DNA repair genes: association with chemotherapy exposure and survival in sporadic ovarian and peritoneal carcinomas
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DOI：
10.1186/1476-4598-8-48
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发表时间：
2009-07-14
期刊：
影响因子：
37.3
通讯作者：
Welcsh, Piri
中科院分区：
文献类型：
--
作者：
Swisher, Elizabeth M.;Gonzalez, Rachel M.;Welcsh, Piri
背景：DNA 修复基因关键性地调节细胞对化疗的反应，这些基因的表观遗传调节可能会受到化疗暴露的影响。 BRCA1 和 BRCA2 的恢复介导复发性 BRCA1 和 BRCA2 突变遗传性卵巢癌对铂类化疗的耐药性。我们评估了 115 例散发性原发性卵巢癌中的 BRCA1、BRCA2 和 MLH1 蛋白表达，其中 31 例具有化疗后收集的配对复发性肿瘤。此外，我们评估了 BRCA1、MLH1 或 FANCF 的启动子甲基化是否影响化疗反应或解释化疗后蛋白质表达的变化。结果：在 115 例原发性散发性卵巢癌中，39 例 (34%) 具有低 BRCA1 蛋白，49 例 (42%) 具有低 BRCA2 表达。 BRCA1 和 BRCA2 蛋白表达高度一致 (p < 0.0001)。 MLH1 蛋白丢失发生在 28/115 (24%) 原发性肿瘤中。原发性肿瘤中 BRCA1 蛋白缺失与更好的生存率相关（p = 0.02 对数秩检验），并且在多变量模型中考虑分期或年龄后仍然显着（p = 0.04，Cox 比例风险）。在配对样本中，在配对原发癌中具有低或中等蛋白水平的复发癌中，BRCA1 蛋白表达增加为 13/21 (62%)，BRCA2 蛋白表达增加为 15/21 (71%)。相反，MLH1 表达在复发性癌症中很少下降（1/33，3%）。 MLH1、BRCA1 和 FANCF 启动子甲基化发生在未经化疗的原发性癌、新辅助化疗后或复发性肿瘤中的频率相似。结论：原发性散发性卵巢癌中 BRCA1 低表达与生存期延长相关。复发性卵巢癌在化疗后通常会增加 BRCA1 和/或 BRCA2 蛋白表达，这可能会介导对铂类疗法的耐药性。然而，化疗后这些蛋白质表达的改变通常不是由启动子甲基化介导的，其他调节机制可能导致这些改变。
Background: DNA repair genes critically regulate the cellular response to chemotherapy and epigenetic regulation of these genes may be influenced by chemotherapy exposure. Restoration of BRCA1 and BRCA2 mediates resistance to platinum chemotherapy in recurrent BRCA1 and BRCA2 mutated hereditary ovarian carcinomas. We evaluated BRCA1, BRCA2, and MLH1 protein expression in 115 sporadic primary ovarian carcinomas, of which 31 had paired recurrent neoplasms collected after chemotherapy. Additionally, we assessed whether promoter methylation of BRCA1, MLH1 or FANCF influenced response to chemotherapy or explained alterations in protein expression after chemotherapy exposure.Results: Of 115 primary sporadic ovarian carcinomas, 39 (34%) had low BRCA1 protein and 49 (42%) had low BRCA2 expression. BRCA1 and BRCA2 protein expression were highly concordant (p < 0.0001). MLH1 protein loss occurred in 28/115 (24%) primary neoplasms. BRCA1 protein loss in primary neoplasms was associated with better survival (p = 0.02 Log Rank test) and remained significant after accounting for either stage or age in a multivariate model (p = 0.04, Cox proportional hazards). In paired specimens, BRCA1 protein expression increased in 13/21 (62%) and BRCA2 protein expression increased in 15/21 (71%) of recurrent carcinomas with low or intermediate protein in the paired primary. In contrast MLH1 expression was rarely decreased in recurrent carcinomas (1/33, 3%). Similar frequencies of MLH1, BRCA1, and FANCF promoter methylation occurred in primary carcinomas without previous chemotherapy, after neoadjuvant chemotherapy, or in recurrent neoplasms.Conclusion: Low BRCA1 expression in primary sporadic ovarian carcinoma is associated with prolonged survival. Recurrent ovarian carcinomas commonly have increased BRCA1 and/or BRCA2 protein expression post chemotherapy exposure which could mediate resistance to platinum based therapies. However, alterations in expression of these proteins after chemotherapy are not commonly mediated by promoter methylation, and other regulatory mechanisms are likely to contribute to these alterations.