Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer:: Relationships with abnormal E-cadherin and catenin expression and microsatellite instability
Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer:: Relationships with abnormal E-cadherin and catenin expression and microsatellite instability
复制标题
DOI：
10.1002/ijc.11197
复制
发表时间：
2003-08-20
影响因子：
6.4
通讯作者：
Palacios, J
中科院分区：
文献类型：
--
作者：
Sarrió, D;Moreno-Bueno, G;Palacios, J
乳腺癌中 E-钙粘蛋白 (E-CD) 缺失的原因和功能后果尚不清楚。 E-CD 丢失可能与 APC/β-连环蛋白通路的改变协同作用，从而允许致癌的 β-连环蛋白信号传导。为了检验这一假设，我们分析了一系列 46 例浸润性小叶乳腺癌 (ILC) 中影响 E-CD (CDHI)、APC 和 β-连环蛋白 (CTNNBI) 基因的遗传和表观遗传改变的存在，以及 E-CD、β-和 γ-连环蛋白的免疫组织化学表达。由于 80% 的 ILC 具有 E-CD 表达完全丧失的特征，我们分析了这些肿瘤中导致 E-CD 失活的分子变化。我们发现 46 例病例中有 10 例 (22%) 携带 CDHI 突变，其中 1 例有 2 种不同的突变（其中 1 例是种系突变）。 CDHI 也因杂合性丧失（LOH；30/41，73%）和启动子高甲基化（19/46，41%）而失活。有趣的是，在 ILC 的相应原位病变中也检测到了 LOH 和突变，这意味着这些改变是小叶癌肿瘤发生的早期事件。此外，发现 CDHI 启动子中多态性的存在与 CDHI 突变呈负相关，但与 E-CD 水平无关。接下来我们检查了 APC/β-连环蛋白通路的改变是否也发生在同一系列的 ILC 中。虽然未检测到 CTNNBI 或 APC 突变，但发现了 APC 的启动子甲基化（25/46，52%）和 LOH（7/30，23%）。此外，APC 和 CDHI 的甲基化一致发生。然而，90% 的肿瘤中 β 和 γ 连环蛋白严重减少或缺失，这意味着 CDHI 和 APC 基因的改变不会促进 ILC 中 β 连环蛋白的积累。这些分子改变与微卫星不稳定性无关。总之，几种不同的机制（突变、LOH、甲基化）与侵袭性和原位小叶乳腺癌中频繁的 CDHI 失活有关。相同的肿瘤还表现出 APC 基因的遗传和表观遗传改变。然而，改变的 CDHI 和 APC 基因不会促进这种肿瘤类型中 β-连环蛋白的积累。 (C) 2003 Wiley-Liss, Inc.
The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDHI), APC and beta-catenin (CTNNBI) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDHI, including 1 case with 2 different mutations (1 of which was germline). CDHI was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDHI promoter was found to be inversely correlated with CDHI mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNBI or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDHI occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDHI and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDHI inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDHI and APC genes do not promote beta-catenin accumulation in this tumor type. (C) 2003 Wiley-Liss, Inc.