Faculty of Medicine/Dr Sardjito Hospital, Universitas Gadjah Mada,Yogyakarta, Indonesia.
Mol Cancer. 2011 May 2;10:48. doi: 10.1186/1476-4598-10-48.
Undifferentiated nasopharyngeal carcinoma (NPC) is strongly related to Epstein-Barr virus (EBV) infection, allowing aberrant antibodies against EBV and viral DNA load as screening tools in high risk populations. Methylation analysis in the promoter of tumor suppressor genes (TSGs) may serve as a complementary marker for identifying early cases. This study determined methylation status of multiple TSGs and evaluated whether it may improve early detection.
Nasopharyngeal brushings were taken from 53 NPC patients, 22 high risk subjects and 25 healthy EBV carriers. Corresponding NPC paraffin tissue was included. DNA was bisulfite-modified preceding analysis by methylation-specific PCR (MSP). Ten TSGs were studied.
NPC paraffin and brushing DNA revealed an 81.8% concordance so that MSP analysis was done using either one of both specimens. NPC samples showed methylation for individual TSGs (DAPK1 79.2%, CDH13 77.4%, DLC1 76.9%, RASSF1A 75.5%, CADM1 69.8%, p16 66.0%, WIF1 61.2%, CHFR 58.5%, RIZ1 56.6% and RASSF2A 29.2%). High risk individuals, having elevated EBV IgA and viral load, showed high frequency of methylation of CDH13, DAPK1, DLC1 and CADM1, but low frequency of methylation of p16 and WIF1 and undetectable methylation of RASSF1A, CHFR, RIZ1 and RASSF2A. Healthy subjects showed similar patterns as high risk individuals. A combination of RASSF1A and p16 gave good discrimination between NPC and non-NPC, but best results were combined analysis of five methylation markers (RASSF1A, p16, WIF1, CHFR and RIZ1) with detection rate of 98%.
Multiple marker MSP is proposed as a complementary test for NPC risk assessment in combination with EBV-based markers.
未分化型鼻咽癌（NPC）与 EBV 感染密切相关，这使得针对 EBV 的异常抗体和病毒 DNA 载量成为高危人群的筛查工具。肿瘤抑制基因（TSG）启动子中的甲基化分析可能作为识别早期病例的补充标志物。本研究检测了多个 TSG 的甲基化状态，评估其是否有助于提高早期检测率。
采集 53 例 NPC 患者、22 例高危人群和 25 例 EBV 携带的鼻咽拭子。包含相应的 NPC 石蜡组织。在进行甲基化特异性 PCR（MSP）分析前，对 DNA 进行亚硫酸氢盐修饰。研究了 10 个 TSG。
NPC 石蜡和刷检 DNA 的一致性为 81.8%，因此可使用其中一种标本进行 MSP 分析。NPC 样本中存在多个 TSG 的甲基化（DAPK1 79.2%、CDH13 77.4%、DLC1 76.9%、RASSF1A 75.5%、CADM1 69.8%、p16 66.0%、WIF1 61.2%、CHFR 58.5%、RIZ1 56.6%和 RASSF2A 29.2%）。EBV IgA 和病毒载量升高的高危人群中，CDH13、DAPK1、DLC1 和 CADM1 的甲基化频率较高，但 p16 和 WIF1 的甲基化频率较低，RASSF1A、CHFR、RIZ1 和 RASSF2A 则无法检测到甲基化。健康受试者的模式与高危人群相似。RASSF1A 和 p16 的联合检测可较好地区分 NPC 和非 NPC，但最佳结果是联合分析五个甲基化标志物（RASSF1A、p16、WIF1、CHFR 和 RIZ1），其检出率为 98%。
建议将多重标记 MSP 作为一种补充性检测方法，与 EBV 标志物联合应用，用于 NPC 风险评估。
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