AUTHOR=Zhu Chaofan , Zhang Meiying , Wang Qian , Jen Jin , Liu Baoguo , Guo Mingzhou 

TITLE=Intratumor Epigenetic Heterogeneity—A Panel Gene Methylation Study in Thyroid Cancer

JOURNAL=Frontiers in Genetics

VOLUME=12

YEAR=2021

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2021.714071

DOI=10.3389/fgene.2021.714071

ISSN=1664-8021

ABSTRACT=<sec><title>Background</title><p>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.</p></sec><sec><title>Methods</title><p>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.</p></sec><sec><title>Results</title><p>Five genes (<italic>AP2</italic>, <italic>CDH1</italic>, <italic>DACT2</italic>, <italic>HIN1</italic>, and <italic>RASSF1A</italic>) are found frequently methylated (&gt;30%) in thyroid cancer. The five genes panel is used for further epigenetic heterogeneity analysis. <italic>AP2</italic> methylation is associated with gender (<italic>P</italic> &lt; 0.05), <italic>DACT2</italic> methylation is associated with age, gender and tumor size (all <italic>P</italic> &lt; 0.05), HIN1 methylation is associated to tumor size (<italic>P</italic> &lt; 0.05) and extra-thyroidal extension (<italic>P</italic> &lt; 0.01). <italic>RASSF1A</italic> methylation is associated with lymph node metastasis (<italic>P</italic> &lt; 0.01). For heterogeneity analysis, <italic>AP2</italic> methylation heterogeneity <italic>is</italic> associated with tumor size (<italic>P</italic> &lt; 0.01), <italic>CDH1</italic> methylation heterogeneity is associated with lymph node metastasis (<italic>P</italic> &lt; 0.05), <italic>DACT2</italic> methylation heterogeneity is associated with tumor size (<italic>P</italic> &lt; 0.01), <italic>HIN1</italic> methylation heterogeneity is associated with tumor size and extra-thyroidal extension (all <italic>P</italic> &lt; 0.01). The multivariable analysis suggested that the risk of lymph node metastasis is 2.5 times in <italic>CDH1</italic> heterogeneous methylation group (<italic>OR</italic> = 2.512, 95% CI 1.135, 5.557, <italic>P</italic> = 0.023). The risk of extra-thyroidal extension is almost 3 times in <italic>HIN1</italic> heterogeneous methylation group (<italic>OR</italic> = 2.607, 95% CI 1.138, 5.971, <italic>P</italic> = 0.023).</p></sec><sec><title>Conclusion</title><p>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.</p></sec>