Association between DNA methylation profile and malignancy in follicular-patterned thyroid neoplasms

Abstract

Molecular differentiation between benign (follicular thyroid adenoma (FTA)) and malignant (follicular thyroid carcinoma (FTC)) thyroid neoplasms is challenging. Here, we explored the genome-wide DNA methylation profile of FTA (n.10) and FTC (n.11) compared to normal thyroid (NT) (n.7) tissues. FTC featured 3564 differentially methylated CpGs (DMCpG), most (84%) of them hypermethylated, with respect to normal controls. At the principal component analysis (PCA), the methylation profile of FTA occupied an intermediate position between FTC and normal tissue. A large fraction (n. 2385) of FTC-associated DMCpG was related (intragenic or within 1500 bp from the transcription start site) to annotated genes (n. 1786). FTC-hypermethylated genes were enriched for targets of the Polycomb transcriptional repressor complex and the specific histone H3 marks (H3K4me2/me3-H3K27me3) found in chromatin domains known as ‘bivalent’. Transcriptome profiling by RNAseq showed that 7.9% of the DMCpGs-associated genes were differentially expressed in FTC compared to NT, suggesting that altered DNA methylation may contribute to their altered expression. Overall, this study suggests that perturbed DNA methylation, in particular hypermethylation, is a component of the molecular mechanisms leading to the formation of FTC and that DNA methylation profiling may help differentiating FTCs from their benign counterpart.

DNA methylation in thyroid cancer

“…Only the study by Rodríguez-Rodero et al identified more hypermethylations than hypomethylations, which could be explained by the low number of analyzed PTCs (Rodríguez-Rodero et al 2013). In contrast to PTC, FTC exhibits more hypermethylations than hypomethylations (most of them outside promoter regions) (Rodríguez-Rodero et al 2013, Mancikova et al 2014, Bisarro dos Reis et al 2017, Affinito et al 2019 as well as follicular adenomas (FA), although the number of DNA alterations in these benign tumors is low, thus resembling normal thyroid methylomes ( Supplementary Fig. 3).…”

Research Progress of DNA Methylation in Thyroid Cancer

“…Also, others identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in FTC and 16.67% (n = 5 of 30) in ATC [62]. Studies found a more detailed analysis showing that 53.9% of the hypermethylated and 81.5% of the hypomethylated CpG sites identified in differentiated primary tumors (PTCs and FTCs) were also present in differentiated thyroid carcinoma-derived cancer cell [61]. Aside from that, COL4A2 was hypermethylated in 56% of the FTC samples by array measurement in the discovery series [57,63].…”

“…Moreover, 3564 differentially methylated CpGs (DMCpG) were detected in FTC and 84% hypermethylated with respect to normal controls. It is suggested that perturbed DNA methylation, in particular hypermethylation, is a component of the molecular mechanisms leading to FTC formation and that DNA methylation profiling might help in differentiating FTCs from their benign counterpart [61]. Also, others identified the presence of RASAL1 mutations, with a prevalence of 4.88% (n = 2 of 41) in FTC and 16.67% (n = 5 of 30) in ATC [62].…”

Association of DNA Promoter Methylation and BRAF Mutation in Thyroid Cancer

“…To investigate the methylation changes, a number of studies were conducted using the candidate gene approach utilizing amplicon sequencing [ 35 , 36 ], methylation-specific PCR [ 37 , 38 , 39 , 40 , 41 , 42 ], or qPCR [ 43 , 44 ]. There are also some genome-wide methylation studies using microarray on 27K BeadChip [ 45 , 46 ] or 450K BeadChip [ 29 , 47 , 48 , 49 , 50 ]. Methylation is also achieved on a genome-wide level using RRBS sequencing [ 51 , 52 ].…”