Zhu Chaofan, Zhang Meiying, Wang Qian, Jen Jin, Liu Baoguo, Guo Mingzhou
Department of Head and Neck Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.
Front Genet. 2021 Sep 3;12:714071. doi: 10.3389/fgene.2021.714071. eCollection 2021.
Thyroid cancer (TC) is the most common endocrine malignancy, and the incidence is increasing very fast. Surgical resection and radioactive iodine ablation are major therapeutic methods, however, around 10% of differentiated thyroid cancer and all anaplastic thyroid carcinoma (ATC) are failed. Comprehensive understanding the molecular mechanisms may provide new therapeutic strategies for thyroid cancer. Even though genetic heterogeneity is rigorously studied in various cancers, epigenetic heterogeneity in human cancer remains unclear.
A total of 405 surgical resected thyroid cancer samples were employed (three spatially isolated specimens were obtained from different regions of the same tumor). Twenty-four genes were selected for methylation screening, and frequently methylated genes in thyroid cancer were used for further validation. Methylation specific PCR (MSP) approach was employed to detect the gene promoter region methylation.
Five genes (, , , , and ) are found frequently methylated (>30%) in thyroid cancer. The five genes panel is used for further epigenetic heterogeneity analysis. methylation is associated with gender ( < 0.05), methylation is associated with age, gender and tumor size (all < 0.05), HIN1 methylation is associated to tumor size ( < 0.05) and extra-thyroidal extension ( < 0.01). methylation is associated with lymph node metastasis ( < 0.01). For heterogeneity analysis, methylation heterogeneity associated with tumor size ( < 0.01), methylation heterogeneity is associated with lymph node metastasis ( < 0.05), methylation heterogeneity is associated with tumor size ( < 0.01), methylation heterogeneity is associated with tumor size and extra-thyroidal extension (all < 0.01). The multivariable analysis suggested that the risk of lymph node metastasis is 2.5 times in heterogeneous methylation group ( = 2.512, 95% CI 1.135, 5.557, = 0.023). The risk of extra-thyroidal extension is almost 3 times in heterogeneous methylation group ( = 2.607, 95% CI 1.138, 5.971, = 0.023).
Five of twenty-four genes were found frequently methylated in human thyroid cancer. Based on 5 genes panel analysis, epigenetic heterogeneity is an universal event. Epigenetic heterogeneity is associated with cancer development and progression.
甲状腺癌（TC）是最常见的内分泌恶性肿瘤，其发病率正迅速上升。手术切除和放射性碘消融是主要的治疗方法，然而，约10%的分化型甲状腺癌和所有未分化甲状腺癌（ATC）治疗失败。全面了解分子机制可能为甲状腺癌提供新的治疗策略。尽管在各种癌症中对基因异质性进行了深入研究，但人类癌症中的表观遗传异质性仍不清楚。
共使用了405例手术切除的甲状腺癌样本（从同一肿瘤的不同区域获取三个空间分离的标本）。选择24个基因进行甲基化筛查，并对甲状腺癌中频繁甲基化的基因进行进一步验证。采用甲基化特异性PCR（MSP）方法检测基因启动子区域甲基化。
发现五个基因（、、、和）在甲状腺癌中频繁甲基化（>30%）。这五个基因组合用于进一步的表观遗传异质性分析。甲基化与性别相关（<0.05），甲基化与年龄、性别和肿瘤大小相关（均<0.05），HIN1甲基化与肿瘤大小相关（<0.05）和甲状腺外扩展相关（<0.01）。甲基化与淋巴结转移相关（<0.01）。对于异质性分析，甲基化异质性与肿瘤大小相关（<0.01），甲基化异质性与淋巴结转移相关（<0.05），甲基化异质性与肿瘤大小相关（<0.01），甲基化异质性与肿瘤大小和甲状腺外扩展相关（均<0.01）。多变量分析表明，甲基化异质性组中淋巴结转移风险是2.5倍（=2.512，95%CI 1.135，5.557，=0.023）。甲状腺外扩展风险在甲基化异质性组中几乎是3倍（=2.607，95%CI 1.138，5.971，=0.023）。
在人类甲状腺癌中发现24个基因中有5个频繁甲基化。基于5个基因组合分析，表观遗传异质性是一个普遍现象。表观遗传异质性与癌症的发生发展相关。
