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Alterations of regulatory factors and DNA methylation pattern in thyroid cancer.
- Source :
-
Cancer biomarkers : section A of Disease markers [Cancer Biomark] 2020; Vol. 28 (2), pp. 255-268. - Publication Year :
- 2020
-
Abstract
- Purpose: DNA methylation plays an important role in thyroid oncogenesis. The aim of this study was to investigate the connection between global and local DNA methylation status and to establish the levels of important DNA methylation regulators (TET family and DNMT1) in thyroid tumours: follicular adenoma-FA, papillary thyroid carcinoma-PTC (classic papillary thyroid carcinoma-cPTC and papillary thyroid carcinoma follicular variant fvPTC).<br />Methods: Global DNA methylation profile in thyroid tumours tissue (41 paired samples) was assessed by 5-methylcytosine and 5-hydroxymethylcytosine levels evaluation (ELISA), along with TETs and DNMT1 genes expression quantification. Also, it was investigated for the first time TET1 and TET2 promoter's methylation in thyroid tumours. BRAF V600E mutation and RET/PTC translocation testing were performed on all investigated samples. In vitro studies upon DNA methylation in K1 thyroid cancer cells were performed with demethylating agents (5-AzaC and vitamin C).<br />Results: TET1 and TET2 displayed a significantly reduced gene expression level in PTC, while DNMT1 gene presented a high level of expression. PTC samples presented increased levels of 5-methylcytosine and low levels of 5-hydroxymethylcytosine. 5-methylcytosine levels were associated with TET1/TET2 expression levels. TET1 gene expression was significantly lower in patients positive for BRAF mutation and with RET/PTC rearrangement. TET2 gene was found hypermethylated in thyroid carcinoma patients overall, especially in PTC-follicular variant samples (p= 0.0002), where TET2 gene expression levels were significantly reduced (p= 0.0031). Furthermore, the data indicate for all thyroid cancer patients a good sensitivity (81.08%) and specificity (86.49%) regarding the use of TET1 (p< 0.0001), and TET2 (71.79%, 64.10%, p= 0.0001) hypermethylation as biomarkers for thyroid oncogenesis.<br />Conclusions: These results suggest that TET1/TET2 gene expression and methylation may serve as potential diagnostic tools for thyroid neoplasia. Our study showed that the methylation of TET1 increases in malignant thyroid tumours. fvPTC patients presented lower methylation levels compared to cPTC and could be a discriminatory factor between two cancer types and benign lesions. TET2 is a poorer discriminator between FA and fvPTC, but it can be useful for cPTC identification. K1-cells treated with demethylating agents showed a demethylation effect, especially upon TET2 gene. The cumulative effect of L-AA and 5-AzaC proved to have a potent combined demethylating effect on genes promoter's activation and could open new perspectives for thyroid cancer therapy.
- Subjects :
- Adenocarcinoma, Follicular diagnosis
Adenocarcinoma, Follicular drug therapy
Adenocarcinoma, Follicular pathology
Adolescent
Adult
Aged
Antineoplastic Combined Chemotherapy Protocols pharmacology
Antineoplastic Combined Chemotherapy Protocols therapeutic use
Ascorbic Acid pharmacology
Ascorbic Acid therapeutic use
Azacitidine pharmacology
Azacitidine therapeutic use
Carcinogenesis genetics
Cell Line, Tumor
DNA (Cytosine-5-)-Methyltransferase 1 genetics
DNA Methylation drug effects
DNA-Binding Proteins genetics
Dioxygenases
Drug Screening Assays, Antitumor
Epigenesis, Genetic drug effects
Feasibility Studies
Female
Gene Expression Regulation, Neoplastic drug effects
Humans
Male
Middle Aged
Mixed Function Oxygenases genetics
Promoter Regions, Genetic genetics
Proto-Oncogene Proteins genetics
Sensitivity and Specificity
Thyroid Cancer, Papillary diagnosis
Thyroid Cancer, Papillary drug therapy
Thyroid Cancer, Papillary pathology
Thyroid Gland pathology
Thyroid Neoplasms diagnosis
Thyroid Neoplasms drug therapy
Thyroid Neoplasms pathology
Young Adult
Adenocarcinoma, Follicular genetics
Biomarkers, Tumor genetics
DNA Methylation genetics
Thyroid Cancer, Papillary genetics
Thyroid Neoplasms genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1875-8592
- Volume :
- 28
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Cancer biomarkers : section A of Disease markers
- Publication Type :
- Academic Journal
- Accession number :
- 32390600
- Full Text :
- https://doi.org/10.3233/CBM-190871