Inactivation of tumor suppressor genes, such as RAP1GAP, by hypermethylation of their regulatory region can give rise to thyroid tumors. The aim of this study was to investigate the expression of the RAP1GAP gene and the DNA methylation patterns of its CpG74_a, CpG74_b, and CpG24 in an Iranian population with differentiated thyroid cancer (DTC). In this study, 160 individuals who underwent thyroidectomy in the Tehran Erfan Hospital between 2018 and 2020 were selected. DNA methylation patterns of selected CpG islands (CpG74_a, CpG74_b, and CpG24) were determined using methylation-specific PCR. The mRNA expression and protein level of ­RAP1GAP were also evaluated. SW1736 and B-CPAP cells were treated with 5-aza-2′-deoxycytidine (5-Aza) to demethylate these regions. The hypermethylation rates of CpG74_a and CpG24 in DTC samples were significantly higher than in the control. The mRNA expression and protein level of ­RAP1GAP were significantly decreased in the DTC group. In the DTC group, hypermethylation in CpG74_a was correlated with decreasing RAP1GAP expression (R²: 0.34; p = 0.043). CpG74_a with a specificity of 86.4% has significant prediction power to distinguish between DTC and normal thyroid tissues. Additionally, hypermethylation of CpG74_a was significantly associated with higher tumor stages (stage III-IV: 77%; stage I-II: 23%; p = 0.012). Increasing expression of RAP1GAP after demethylation with 15 µM of 5-Aza was observed in both cell lines. These results indicate that DNA hypermethylation in CpG74_a can be considered as an epigenetic biomarker in DTC.
Cytogenet Genome Res

中文翻译：

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RAP1GAP 作为肿瘤抑制基因，在分化的甲状腺癌中受 DNA 甲基化调控

抑癌基因（如RAP1GAP）通过其调节区的高甲基化失活可引起甲状腺肿瘤。本研究的目的是调查的表达RAP1GAP基因及其CpG74的DNA甲基化模式_一，CpG74 _b与分化型甲状腺癌（DTC）的伊朗人口，和CpG24。在这项研究中，选择了 2018 年至 2020 年在德黑兰埃尔凡医院接受甲状腺切除术的 160 名患者。所选 CpG 岛的 DNA 甲基化模式（CpG74 _a、CpG74 _b和 CpG24) 使用甲基化特异性 PCR 测定。还评估了 RAP1GAP 的 mRNA 表达和蛋白质水平。SW1736 和 B-CPAP 细胞用 5-aza-2'-deoxycytidine (5-Aza) 处理以使这些区域去甲基化。CpG74的甲基化率_一和CpG24在DTC样品比对照显著较高。DTC组RAP1GAP的mRNA表达和蛋白水平显着降低。在 DTC 组中，CpG74a 中_的高甲基化与RAP1GAP表达的降低相关（R ²：0.34；p = 0.043）。CpG74_一86.4% 的特异性具有显着的区分 DTC 和正常甲状腺组织的预测能力。此外，CpG74a_的高甲基化与较高的肿瘤分期显着相关（III-IV 期：77%；I-II 期：23%；p = 0.012）。在两种细胞系中均观察到用 15 µM 5-Aza 去甲基化后RAP1GAP 的表达增加。这些结果表明 CpG74a 中_的DNA 高甲基化可被视为 DTC 中的表观遗传生物标志物。
细胞遗传基因组研究