Abstract
BackgroundThyroid 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.MethodsA 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.ResultsFive genes (AP2, CDH1, DACT2, HIN1, and RASSF1A) are found frequently methylated (>30%) in thyroid cancer. The five genes panel is used for further epigenetic heterogeneity analysis. AP2 methylation is associated with gender (P < 0.05), DACT2 methylation is associated with age, gender and tumor size (all P < 0.05), HIN1 methylation is associated to tumor size (P < 0.05) and extra-thyroidal extension (P < 0.01). RASSF1A methylation is associated with lymph node metastasis (P < 0.01). For heterogeneity analysis, AP2 methylation heterogeneity is associated with tumor size (P < 0.01), CDH1 methylation heterogeneity is associated with lymph node metastasis (P < 0.05), DACT2 methylation heterogeneity is associated with tumor size (P < 0.01), HIN1 methylation heterogeneity is associated with tumor size and extra-thyroidal extension (all P < 0.01). The multivariable analysis suggested that the risk of lymph node metastasis is 2.5 times in CDH1 heterogeneous methylation group (OR = 2.512, 95% CI 1.135, 5.557, P = 0.023). The risk of extra-thyroidal extension is almost 3 times in HIN1 heterogeneous methylation group (OR = 2.607, 95% CI 1.138, 5.971, P = 0.023).ConclusionFive 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.
Highlights
Thyroid cancer (TC) is the most common endocrine malignancy and the incidence is 3.4% of all cancers (Seib and Sosa, 2019)
The methylation status of AP2, CDH1, DACT2, HIN1, and RASSF1A genes is examined by Methylationspecific PCR (MSP)
DACT2 methylation is associated with age, gender and tumor size, while no association is found between DACT2 methylation and tumor location, TNM stage, lymph node metastasis, and extra-thyroidal extension
Summary
Thyroid cancer (TC) is the most common endocrine malignancy and the incidence is 3.4% of all cancers (Seib and Sosa, 2019). Surgical resection and radioactive iodine ablation are major therapeutic strategies for thyroid cancer. In the last 30 years, genetic study suggests that the frequency of somatic mutations is relatively low in thyroid cancer (Mazzaferri, 1999). Mutations in different signaling pathways were found by genomic study in thyroid cancer (Vogelstein et al, 2013; Cha and Koo, 2016). Subpopulations of cancer cells with distinct phenotypic and molecular features within a tumor are called intratumor heterogeneity (ITH) (Bedard et al, 2013). Researchers mainly focused on mutational activation of oncogenes or inactivation of tumor-suppressor genes (TSGs). Surgical resection and radioactive iodine ablation are major therapeutic methods, 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
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