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Alterations of regulatory factors and DNA methylation pattern in thyroid cancer
- Source :
- Cancer Biomarkers. 28:255-268
- Publication Year :
- 2020
- Publisher :
- IOS Press, 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). 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). 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. 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 :
- Male
Cancer Research
endocrine system diseases
Carcinogenesis
Thyroid Gland
Ascorbic Acid
medicine.disease_cause
Epigenesis, Genetic
Mixed Function Oxygenases
Adenocarcinoma, Follicular
Antineoplastic Combined Chemotherapy Protocols
Promoter Regions, Genetic
Thyroid cancer
05 social sciences
Thyroid
Global DNA Methylation Profile
General Medicine
Methylation
Middle Aged
DNA-Binding Proteins
Gene Expression Regulation, Neoplastic
medicine.anatomical_structure
Oncology
Thyroid Cancer, Papillary
DNA methylation
Azacitidine
Female
050104 developmental & child psychology
Adult
DNA (Cytosine-5-)-Methyltransferase 1
endocrine system
Adolescent
Sensitivity and Specificity
Dioxygenases
Thyroid carcinoma
Young Adult
Cell Line, Tumor
Proto-Oncogene Proteins
Biomarkers, Tumor
Genetics
medicine
Humans
0501 psychology and cognitive sciences
Thyroid Neoplasms
Aged
0505 law
business.industry
Cancer
DNA Methylation
medicine.disease
050501 criminology
Cancer research
Feasibility Studies
Drug Screening Assays, Antitumor
business
Subjects
Details
- ISSN :
- 18758592 and 15740153
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- Cancer Biomarkers
- Accession number :
- edsair.doi.dedup.....5478b568f2d65a2697c412d3a67054c1