Zhu X, Shan L, Wang F, Wang J, Wang F, Shen G, Liu X, Wang B, Yuan Y, Ying J, Yang H
Department of Pathology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China.
Breast Cancer Res Treat. 2015 Apr;150(3):479-86. doi: 10.1007/s10549-015-3338-y. Epub 2015 Mar 18.
Paraffin sections from 239 cases of surgical resected mammary gland carcinomas were assessed to determine the role of BRCA1 gene methylation in sporadic triple-negative breast cancer and to evaluate the relationship between BRCA1 gene methylation and clinicopathologic features of triple-negative breast cancer in the National Cancer Center, China. Diagnostic tissues collected from patients received mastectomy in the National Cancer Center from January 1, 1999 to December 31, 2008 were reviewed. Tissue microarrays were constructed using 239 triple-negative breast cancer cases and stained with estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, cytokeratin 5/6, and epidermal growth factor receptor. Methylation status of the BRCA1 promoter was measured by methylation-specific PCR and analyzed against clinicopathologic characteristics, subtypes, and prognosis using standard statistical methods. Among the 239 triple-negative breast cancer cases, 137 (57.3 %) showed methylation of the BRCA1. According to the immunohistochemistry results, triple-negative breast cancer cases were classified into basal-like breast cancer (60.7 %) and non-basal-like breast cancer (39.3 %). The frequency of BRCA1 methylation was significantly higher in basal-like breast cancer subtype (71.7 %) than the non-basal subtype (35.1 %). Thus, BRCA1 methylation is statistically significantly correlated with basal-like breast cancer subtype (p < 0.001). Multivariate analyses further showed that BRCA1 promoter methylation is an independently predictor of overall survival (p = 0.023; HR 2.32; 95 % CI 1.12-4.81) and disease-free survival (p = 0.022; HR 2.36; 95 % CI 1.13-4.90) in triple-negative breast cancer. Here we demonstrated that epigenetic alteration of key tumor suppressor gene can be a promising biomarker for the prognosis of triple-negative breast cancer/basal-like breast cancer. Specifically our finding revealed that BRCA1 methylation is closely associated with a significant decrease in overall survival and disease-free survival, highlighting BRCA1 promoter methylation as promising and powerful biomarkers for effect and better prognosis of DNA damaging agents for triple-negative breast cancer/basal-like breast cancer.
对239例手术切除的乳腺癌石蜡切片进行评估，以确定BRCA1基因甲基化在散发性三阴性乳腺癌中的作用，并在中国国家癌症中心评估BRCA1基因甲基化与三阴性乳腺癌临床病理特征之间的关系。回顾了1999年1月1日至2008年12月31日在国家癌症中心接受乳房切除术患者的诊断组织。使用239例三阴性乳腺癌病例构建组织微阵列，并用雌激素受体、孕激素受体、人表皮生长因子受体2、细胞角蛋白5/6和表皮生长因子受体进行染色。通过甲基化特异性PCR检测BRCA1启动子的甲基化状态，并使用标准统计方法针对临床病理特征、亚型和预后进行分析。在239例三阴性乳腺癌病例中，137例（57.3%）显示BRCA1甲基化。根据免疫组织化学结果，三阴性乳腺癌病例分为基底样乳腺癌（60.7%）和非基底样乳腺癌（39.3%）。基底样乳腺癌亚型中BRCA1甲基化频率（71.7%）显著高于非基底亚型（35.1%）。因此，BRCA1甲基化与基底样乳腺癌亚型在统计学上显著相关（p<0.001）。多变量分析进一步表明，BRCA1启动子甲基化是三阴性乳腺癌总生存期（p=0.023；HR 2.32；95%CI 1.12-4.81）和无病生存期（p=0.022；HR 2.36；95%CI 1.13-4.90）的独立预测因子。在此我们证明关键肿瘤抑制基因的表观遗传改变可能是三阴性乳腺癌/基底样乳腺癌预后的一个有前景的生物标志物。具体而言，我们的发现表明BRCA1甲基化与总生存期和无病生存期的显著降低密切相关，突出了BRCA1启动子甲基化作为三阴性乳腺癌/基底样乳腺癌DNA损伤剂疗效和更好预后的有前景且强大的生物标志物。
