Aberrant Keap1 methylation in breast cancer and association with clinicopathological features
Aberrant Keap1 methylation in breast cancer and association with clinicopathological features
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DOI：
10.4161/epi.23319
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发表时间：
2013-01-01
期刊：
影响因子：
3.7
通讯作者：
Parrella, Paola
中科院分区：
文献类型：
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作者：
Barbano, Raffaela;Muscarella, Lucia Anna;Parrella, Paola
Keap 1（Kelch-like ECH-associated protein 1）是一种衔接蛋白，在氧化应激条件下介导调节细胞存活和凋亡的基因的泛素化/降解。我们采用甲基化特异性定量PCR（QMSP）检测了102例原发性乳腺癌、14例浸润前病变、38例配对正常乳腺组织和6例乳房缩小术后正常乳腺组织中KEAP 1启动子的甲基化状态。在102例原发性乳腺癌病例中的52例（51%）和14例浸润前病变中的10例（71%）中检测到异常启动子甲基化。通过基于荧光的直接测序分析，在20例乳腺癌病例中未发现KEAP 1基因突变。与三阴性乳腺癌（35%）相比，ER阳性-HER 2阴性肿瘤（66.7%）患者亚组的甲基化更常见（p = 0.05，卡方检验）。通过RECPA M多变量统计分析研究了Er、PgR、Her 2表达和KEAP 1甲基化之间的相互作用对死亡率的影响，确定了不同死亡率风险下的4种预后类别。KEAP 1甲基化的三阴性乳腺癌患者的死亡风险高于非三阴性乳腺癌患者（HR = 14.73，95%CI：3.65-59.37）。单变量和多变量考克斯回归分析均显示，KEAP 1甲基化与接受表阿霉素/环磷酰胺和多西他赛序贯化疗的患者更好的无进展生存期相关（HR = 0.082; 95% CI：0.007-0.934）。这些结果表明KEAP 1基因启动子甲基化异常参与乳腺癌的发生。此外，识别KEAP 1表观遗传异常的患者可能有助于乳腺癌患者的疾病进展预测。
Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein that mediates the ubiquitination/degradation of genes regulating cell survival and apoptosis under oxidative stress conditions. We determined methylation status of the KEAP1 promoter in 102 primary breast cancers, 14 pre-invasive lesions, 38 paired normal breast tissues and 6 normal breast from reductive mammoplasty by quantitative methylation specific PCR (QMSP). Aberrant promoter methylation was detected in 52 out of the 102 primary breast cancer cases (51%) and 10 out of 14 pre-invasive lesions (71%). No mutations of the KEAP1 gene were identified in the 20 breast cancer cases analyzed by fluorescence based direct sequencing. Methylation was more frequent in the subgroup of patients identified as ER positive-HER2 negative tumors (66.7%) as compared with triple-negative breast cancers (35%) (p = 0.05, Chi-square test). The impact of the interactions between Er, PgR, Her2 expression and KEAP1 methylation on mortality was investigated by RECPA M multivariable statistical analysis, identifying four prognostic classes at different mortality risks. Triple-negative breast cancer patients with KEAP1 methylation had higher mortality risk than patients without triple-negative breast cancer (HR = 14.73, 95% CI: 3.65-59.37). Both univariable and multivariable COX regressions analyses showed that KEAP1 methylation was associated with a better progression free survival in patients treated with epirubicin/cyclophosfamide and docetaxel as sequential chemotherapy (HR = 0.082; 95% CI: 0.007-0.934). These results indicate that aberrant promoter methylation of the KEAP1 gene is involved in breast cancerogenesis. In addition, identifying patients with KEAP1 epigenetic abnormalities may contribute to disease progression prediction in breast cancer patients.