Department of Breast and Endocrine Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
J Hum Genet. 2021 Aug;66(8):785-793. doi: 10.1038/s10038-021-00911-3. Epub 2021 Feb 27.
Aberrant DNA methylation in the BRCA1 promoter region causes epigenetic silencing of BRCA1 gene expression, which is critical for breast cancer development. However, how BRCA1 promoter methylation status alters histological features remains poorly understood. Here, we investigated the possibility to predict BRCA1 promoter methylation status based on the morphological and immunohistochemical features of triple-negative breast cancers (TNBCs). The morphological features of 53 TNBCs were evaluated with hematoxylin-eosin staining, with immunohistochemical staining of BRCA1, androgen receptor, p53, cytokeratin 5/6, and epidermal growth factor receptor. BRCA1 promoter methylation status was used to distinguish BRCA1 promoter-methylated tumors (BPMTs) from BRCA1 promoter-unmethylated tumors (BPUTs) dependent on pathological characteristics. BPMTs comprised approximately 26% of the TNBCs. Immunohistochemical analysis found that BRCA1 protein expression was significantly lower in BPMT compared with BPUT (p = 0.016). Morphologically, BPMTs were associated with high mitotic index (p = 0.017), pushing margin (p = 0.017), a circumscribed growth pattern (p = 0.014), and a syncytial growth pattern (p = 0.034) compared with BPUTs. We then assessed the potential of predicting BRCA1 promoter methylation status by using published score systems based on these morphological characteristics. A receiver operating characteristic analysis showed an area under the curve of 0.80. This study found that BRCA1 promoter methylation status could be derived from morphological features and lower BRCA1 expression of TNBCs, which may help identify suitable cases for target treatment with PARP inhibitors.
BRCA1 启动子区域的异常 DNA 甲基化导致 BRCA1 基因表达的表观遗传沉默，这对乳腺癌的发展至关重要。然而，BRCA1 启动子甲基化状态如何改变组织学特征仍知之甚少。在这里，我们研究了基于三阴性乳腺癌（TNBC）的形态学和免疫组织化学特征来预测 BRCA1 启动子甲基化状态的可能性。通过苏木精-伊红染色评估 53 例 TNBC 的形态特征，并对 BRCA1、雄激素受体、p53、细胞角蛋白 5/6 和表皮生长因子受体进行免疫组织化学染色。根据病理特征，使用 BRCA1 启动子甲基化状态将 BRCA1 启动子甲基化肿瘤（BPMTs）与 BRCA1 启动子未甲基化肿瘤（BPUTs）区分开来。BPMTs 约占 TNBC 的 26%。免疫组织化学分析发现，与 BPUT 相比，BPMT 中的 BRCA1 蛋白表达显著降低（p=0.016）。形态上，与 BPUT 相比，BPMT 与高有丝分裂指数（p=0.017）、推挤边界（p=0.017）、界限分明的生长模式（p=0.014）和合体细胞生长模式（p=0.034）相关。然后，我们评估了使用基于这些形态特征的已发表评分系统预测 BRCA1 启动子甲基化状态的潜力。受试者工作特征分析显示曲线下面积为 0.80。本研究发现，BRCA1 启动子甲基化状态可源自 TNBC 的形态特征和 BRCA1 表达降低，这可能有助于确定适合使用 PARP 抑制剂进行靶向治疗的合适病例。
