The molecular significance of methylated BRCA1 promoter in white blood cells of cancer-free females
The molecular significance of methylated BRCA1 promoter in white blood cells of cancer-free females
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DOI：
10.1186/1471-2407-14-830
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发表时间：
2014-11-17
期刊：
影响因子：
3.8
通讯作者：
Aboussekhra, Abdelilah
中科院分区：
文献类型：
--
作者：
Al-Moghrabi, Nisreen;Nofel, Asmaa;Aboussekhra, Abdelilah
背景：在乳腺癌患者和非癌症女性的外周血细胞DNA中都检测到BRCA1启动子甲基化。然而，这种白细胞(WBC)表观遗传学变化的病理学意义仍然是一个悬而未决的问题。在这项研究中，我们假设，如果BRCA1甲基化反映了患乳腺癌(BC)的风险增加，那么携带BRCA1甲基化的WBC在无癌女性和BC患者中应该表现出类似的分子变化。方法：采用甲基化特异性聚合酶链式反应(MSPR)检测155例乳腺癌患者和143例无癌女性WBC中BRCA1启动子的甲基化。分别使用人乳腺癌EpiTect甲基II特征码聚合酶链式反应阵列和人乳腺癌RT2 Profiler(TM)基因芯片研究乳腺癌相关基因的甲基化状态和表达谱。结果：我们发现14.2%的BC患者和9.1%的无癌女性(携带者)的WBC中含有BRCA1甲基化启动子。有趣的是，66.7%的患者在白细胞和肿瘤中都含有BRCA1甲基化启动子。重要的是，我们已经在患者和携带者的白细胞中发现了9个其他BC相关基因的表观遗传学变化。此外，与对照组相比，患者和携带者的WBC中发现BRCA1和其他15个重要的癌症相关基因的表达存在差异。此外，我们还发现携带者表现出与BC患者和对照组不同的独特的血浆蛋白图谱，与对照组相比，患者和携带者中有10种蛋白质的表达类似。结论：本研究结果表明，WBC中BRCA1启动子的异常甲基化与乳腺癌相关的分子变化之间存在很强的联系，这表明携带者可能容易发生乳腺癌。这提示了在WBC中BRCA1启动子的异常甲基化作为一种强大的非侵入性分子标记在很小的年龄就检测易感个体的潜在用途。
Background: BRCA1 promoter methylation has been detected in DNA from peripheral blood cells of both breast cancer patients and cancer-free females. However, the pathological significance of this epigenetic change in white blood cells (WBC) remains an open question. In this study, we hypothesized that if constitutional BRCA1 methylation reflects an elevated risk for developing breast cancer (BC), WBC that harbor methylated BRCA1 in both cancer-free females and BC patients should exhibit similar molecular changes.Methods: BRCA1 promoter methylation was examined by methylation-specific PCR in WBC from 155 breast cancer patients and 143 cancer-free females. The Human Breast Cancer EpiTect Methyl II Signature PCR Array and The Human Breast Cancer RT2 Profiler (TM) PCR Array were used to study the methylation status and the expression profile of several breast cancer-related genes, respectively. In addition, we used label-free MS-based technique to study protein expression in plasma.Results: We have shown that 14.2% of BC patients and 9.1% of cancer-free females (carriers) harbored methylated BRCA1 promoter in their WBC. Interestingly, 66.7% of patients harbored methylated BRCA1 promoter in both WBC and tumors. Importantly, we have shown the presence of epigenetic changes in 9 other BC-related genes in WBC of both patients and carriers. Additionally, BRCA1 and 15 other important cancer-related genes were found to be differentially expressed in WBC from patients and carriers as compared to controls. Furthermore, we have shown that the carriers exhibited a unique plasma protein pattern different from those of BC patients and controls, with 10 proteins similarly differentially expressed in patients and carriers as compared to controls.Conclusions: The present results suggest the presence of a strong link between aberrant methylation of the BRCA1 promoter in WBC and breast cancer-related molecular changes, which indicate the potential predisposition of the carriers for developing breast cancer. This informs the potential use of the aberrant methylation of BRCA1 promoter in WBC as a powerful non-invasive molecular marker for detecting predisposed individuals at a very early age.