南方医科大学学报

南方医科大学学报 ›› 2022, Vol. 42 ›› Issue (1): 123-129.doi: 10.12122/j.issn.1673-4254.2022.01.15

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HYAL2基因 DNA 甲基化水平可用于甲状腺良恶性肿瘤的鉴别诊断

殷益飞，李 红，杨春生，张敏敏，黄选东，李梦夏，杨蓉西，张正东   

  1. 徐州医科大学附属淮安医院甲状腺乳腺外科，江苏 淮安 223001；南京医科大学公共卫生学院，江苏 南京 211166
  • 出版日期:2022-01-20 发布日期:2022-03-02

Detection of DNA methylation of HYAL2 gene for differentiating malignant from benign thyroid tumors

YIN Yifei, LI Hong, YANG Chunsheng, ZHANG Minmin, HUANG Xuandong, LI Mengxia, YANG Rongxi, ZHANG Zhengdong   

  1. Department of Thyroid and Breast Surgery, Affiliated Huai'an Hospital of Xuzhou Medical University, Huai'an 223001, China; School of Public Health, Nanjing Medical University, Nanjing 211166, China
  • Online:2022-01-20 Published:2022-03-02

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摘要： 目的 通过比较甲状腺良恶性肿瘤组织样本中HYAL2基因CpG位点甲基化水平的差异，评估其作为甲状腺癌鉴别诊断分子标志物的潜在价值。方法 采用飞行时间质谱检测 190对甲状腺乳头状癌（PTC）病例和年龄、性别配对的甲状腺腺瘤中HYAL2基因启动子区域CpG位点的甲基化水平。采用免疫组化检测另外55对匹配的甲状腺良恶性肿瘤患者的HYAL2蛋白表达水平。Logistic回归分析用于评估甲基化水平每降低10%与早期PTC之间的关联并计算比值比（OR）。受试者工作特征曲线及曲线下面积（AUC）用于评估HYAL2基因特定CpG位点甲基化水平改变作为分子标志物的效能。结果 HYAL2_CpG_3位点低甲基化与早期PTC显著相关（OR=1.51，P=0.001），且该关联在Ⅰ期PTC中依旧显著（OR=1.42，P=0.007）。年龄分层分析显示HYAL2_CpG_3甲基化水平降低与早期PTC关联在年龄小于50岁的人群中显著高于高年龄组（OR：1.89 vs 1.37；P<0.05），且低年龄组人群中AUC最高，为0.787。免疫组化结果显示早期PTC中HYAL2蛋白表达水平显著高于甲状腺良性肿瘤。结论 HYAL2基因启动子区域甲基化水平改变与早期PTC的关联，并为DNA甲基化改变作为甲状腺良恶性肿瘤鉴别诊断的标志物提供了新思路。

关键词: HYAL2基因；DNA甲基化；甲状腺肿瘤；鉴别诊断；分子标志物

Abstract: Objective To assess the value of DNA methylation level of HYAL2 gene as a molecular marker for differential diagnosis of malignant and benign thyroid tumors. Methods DNA methylation of HYAL2 gene in tissue specimens of 190 patients with papillary thyroid cancer (PTC) and 190 age- and gender-matched patients with benign thyroid tumors was examined by mass spectrometry, and the protein expression of HYAL2 was detected immunohistochemically for another 55 pairs of patients. Logistic regression analysis was performed to calculate the odds ratio (OR) and evaluate the correlation of per 10% reduction in DNA methylation with PTC. Receiver operating characteristic (ROC) curve analysis was performed and the area under curve (AUC) was calculated to assess the predictive value of alterations in HYAL2 methylation. Results Hypomethylation of HYAL2_CpG_3 was significantly correlated with early-stage PTC (OR=1.51, P=0.001), even in stage I cancer (OR=1.42, P=0.007). Age-stratified analysis revealed a significantly stronger correlation between increased HYAL2_CpG_3 methylation and early-stage PTC in patients below 50 years than in those older than 50 years (OR: 1.89 vs 1.37, P<0.05); ROC analysis also showed a larger AUC of 0.787 in younger patients. The results of immunohistochemistry showed that patients with PTC had significantly higher protein expressions of HYAL2 than patients with benign tumors. Conclusion The alterations of DNA methylation level of HYAL2 gene is significantly correlated with early-stage PTC, suggesting the value of DNA methylation level as a potential biomarker for differentiation of malignant from benign thyroid tumors.

Key words: HYAL2 gene; DNA methylation; thyroid tumor; differential diagnosis; molecular marker