Martín-Sánchez Esperanza, Mendaza Saioa, Ulazia-Garmendia Ane, Monreal-Santesteban Iñaki, Córdoba Alicia, Vicente-García Francisco, Blanco-Luquin Idoia, De La Cruz Susana, Aramendia Ana, Guerrero-Setas David
Cancer Epigenetics Group, Navarrabiomed. Departmento de Salud-UPNA. IdiSNA, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Department of Pathology, Complejo Hospitalario de Navarra, Irunlarrea Road, 3, 31008 Pamplona, Spain.
Clin Epigenetics. 2017 Jan 24;9:7. doi: 10.1186/s13148-016-0309-z. eCollection 2017.
Cadherin-like protein 22 (CDH22) is a transmembrane glycoprotein involved in cell-cell adhesion and metastasis. Its role in cancer is controversial because it has been described as being upregulated in colorectal cancer, whereas it is downregulated in metastatic melanoma. However, its status in breast cancer (BC) is unknown. The purpose of our study was to determine the molecular status and clinical value of in BC.
We observed by immunohistochemistry that the level of CDH22 expression was lower in BC tissues than in their matched adjacent-to-tumour and non-neoplastic tissues from reduction mammoplasties. Since epigenetic alteration is one of the main causes of gene silencing, we analysed the hypermethylation of 3 CpG sites in the promoter by pyrosequencing in a series of 142 infiltrating duct BC cases. was found to be hypermethylated in tumoral tissues relative to non-neoplastic mammary tissues. Importantly, this epigenetic alteration was already present in adjacent-to-tumour tissues, although to a lesser extent than in tumoral samples. Furthermore, gene regulation was dynamically modulated in vitro by epigenetic drugs. Interestingly, hypermethylation in all 3 CpG sites simultaneously, but not expression, was significantly associated with shorter progression-free survival ( 0.015) and overall survival ( = 0.021) in our patient series. Importantly, hypermethylation was an independent factor that predicts poor progression-free survival regardless of age and stage ( = 0.006).
Our results are the first evidence that is hypermethylated in BC and that this alteration is an independent prognostic factor in BC. Thus, hypermethylation could be a potential biomarker of poor prognosis in BC.
类钙黏蛋白22（CDH22）是一种参与细胞间黏附与转移的跨膜糖蛋白。其在癌症中的作用存在争议，因为在结直肠癌中它被描述为上调，而在转移性黑色素瘤中则下调。然而，其在乳腺癌（BC）中的状态尚不清楚。我们研究的目的是确定CDH22在BC中的分子状态和临床价值。
我们通过免疫组织化学观察到，BC组织中CDH22的表达水平低于其匹配的肿瘤旁组织和来自缩乳术的非肿瘤组织。由于表观遗传改变是基因沉默的主要原因之一，我们通过焦磷酸测序分析了142例浸润性导管癌病例系列中CDH22启动子3个CpG位点的高甲基化情况。发现肿瘤组织相对于非肿瘤乳腺组织存在CDH22高甲基化。重要的是，这种表观遗传改变在肿瘤旁组织中已经存在，尽管程度低于肿瘤样本。此外，CDH22基因调控在体外可被表观遗传药物动态调节。有趣的是，在我们的患者系列中，所有3个CpG位点同时发生的CDH22高甲基化而非表达水平，与无进展生存期缩短（P = 0.015）和总生存期缩短（P = 0.021）显著相关。重要的是，无论年龄和分期如何，CDH22高甲基化都是预测无进展生存期差的独立因素（P = 0.006）。
我们的结果首次证明CDH22在BC中发生高甲基化，且这种改变是BC的独立预后因素。因此，CDH22高甲基化可能是BC预后不良的潜在生物标志物。
