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Abstract
Our aim was to comprehensively analyze promoter hypermethylation of a panel of novel and known methylation markers for thyroid neoplasms and to establish their relationship with BRAF mutation and clinicopathologic parameters of thyroid cancer. A cohort of thyroid tumors, consisting of 44 cancers and 44 benign thyroid lesions, as well as 15 samples of adjacent normal thyroid tissue, was evaluated for BRAF mutation and promoter hypermethylation. Genes for quantitative methylation specific PCR (QMSP) were selected by a candidate gene approach. Twenty-two genes were tested: TSHR, RASSF1A, RARβ2, DAPK, hMLH1, ATM, S100, p16, CTNNB1, GSTP1, CALCA, TIMP3, TGFßR2, THBS1, MINT1, CTNNB1, MT1G, PAK3, NISCH, DCC, AIM1 and KIF1A. The PCR-based “mutector assay” was used to detect BRAF mutation. All p values reported are two sided. Considerable overlap was seen in the methylation markers among the different tissue groups. Significantly higher methylation frequency and level were observed for KIF1A and RARß2 in cancer samples compared with benign tumors. A negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARß2 methylation were observed in accordance with previous results. In addition, positive correlation with TIMP3 and a marginal correlation with DCC methylation were observed. The present study constitutes a comprehensive promoter methylation profile of thyroid neoplasia and shows that results must be analyzed in a tissue-specific manner to identify clinically useful methylation markers. Integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive its development.
Disclosure of Potential Conflicts of Interest
This work was supported by National Cancer Institute Grant U01-CA84986, P50 DE019032 and R01 CA107247–04) and a grant from the American Cancer Society (RSG-08–003–01-CCE). The funding agencies had no role in the design of the study, data collection, analysis, interpretation of the results, preparation of the manuscript, or the decision to submit the manuscript for publication. Under a licensing agreement between Oncomethylome Sciences, SA and the Johns Hopkins University, D.S. is entitled to a share of royalty received by the University upon sales of diagnostic products described in this article. D.S. owns Oncomethylome Sciences, SA stock, which is subject to certain restrictions under University policy. D.S. is a paid consultant to Oncomethylome Sciences, SA and is a paid member of the company’s Scientific Advisory Board. The Johns Hopkins University in accordance with its conflict of interest policies is managing the terms of this agreement. Dr. Hoque is a recipient of Young Clinical Scientist Award from the Flight Attendant Medical Research Institute and the Young Investigator Award from the International Association for the Study of Lung Cancer. The other authors have nothing to disclose.
