Prognostic significance of DNMT3A alterations in Middle Eastern papillary thyroid carcinoma.
Adenocarcinoma, Follicular
/ genetics
Adult
Biomarkers, Tumor
/ genetics
Cohort Studies
DNA (Cytosine-5-)-Methyltransferases
/ genetics
DNA Methylation
DNA Methyltransferase 3A
Female
Follow-Up Studies
Gene Expression Regulation, Neoplastic
Humans
Male
Middle Aged
Middle East
Mutation
Prognosis
Promoter Regions, Genetic
Thyroid Cancer, Papillary
/ genetics
Thyroid Neoplasms
/ genetics
Tissue Array Analysis
Tumor Cells, Cultured
5-aza-2′-deoxycytidine
DNMT3A
Exome sequencing
Papillary thyroid carcinoma
Journal
European journal of cancer (Oxford, England : 1990)
ISSN: 1879-0852
Titre abrégé: Eur J Cancer
Pays: England
ID NLM: 9005373
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
12
04
2019
revised:
16
05
2019
accepted:
22
05
2019
pubmed:
8
7
2019
medline:
29
5
2020
entrez:
8
7
2019
Statut:
ppublish
Résumé
Thyroid cancer is the second most common cancer affecting Saudi women after breast cancer, with papillary thyroid carcinoma (PTC) accounting for 80-90% of thyroid cancers. DNA methyltransferases affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers. We sought to evaluate the frequency of DNA methyltransferase 3A (DNMT3A) alterations in a large cohort of >1000 PTC cases using exome sequencing, capture sequencing, immunohistochemistry and methylation-specific polymerase chain reaction. We also performed in vitro analysis to investigate the role of DNMT3A methylation in PTC cell lines. DNMT3A pathogenic mutations were noted in 1.2% (12/1013) of PTC cases. Reduced/loss of DNMT3A expression was seen in 59.8% (579/968) of PTC cases and was significantly associated with the DNMT3A mutation (p = 0.0120). DNMT3A alterations (mutation and/or loss of expression) were associated with aggressive clinical parameters and a poor outcome. The promoter region of the DNMT3A gene was methylated in 57.1% of PTC cases tested and was significantly associated with reduced DNMT3A protein expression (p = 0.0253). Treatment of the methylated PTC cell line with 5-aza-2'-deoxycytidine resulted in demethylation of the DNMT3A gene, leading to restoration of its expression. Demethylation significantly potentiated the TRAIL-mediated apoptosis in PTC cells. Interestingly, silencing of DNMT3A using siRNA suppressed TRAIL-mediated apoptosis. These findings suggest that DNMT3A alterations play an important role in PTC pathogenesis and demethylation agents can be used to restore the function of DNMT3A in a subset of patients with PTC.
Sections du résumé
BACKGROUND
Thyroid cancer is the second most common cancer affecting Saudi women after breast cancer, with papillary thyroid carcinoma (PTC) accounting for 80-90% of thyroid cancers. DNA methyltransferases affect DNA methylation, and it is thought that they play an important role in the malignant transformation of various cancers.
METHODS
We sought to evaluate the frequency of DNA methyltransferase 3A (DNMT3A) alterations in a large cohort of >1000 PTC cases using exome sequencing, capture sequencing, immunohistochemistry and methylation-specific polymerase chain reaction. We also performed in vitro analysis to investigate the role of DNMT3A methylation in PTC cell lines.
RESULTS
DNMT3A pathogenic mutations were noted in 1.2% (12/1013) of PTC cases. Reduced/loss of DNMT3A expression was seen in 59.8% (579/968) of PTC cases and was significantly associated with the DNMT3A mutation (p = 0.0120). DNMT3A alterations (mutation and/or loss of expression) were associated with aggressive clinical parameters and a poor outcome. The promoter region of the DNMT3A gene was methylated in 57.1% of PTC cases tested and was significantly associated with reduced DNMT3A protein expression (p = 0.0253). Treatment of the methylated PTC cell line with 5-aza-2'-deoxycytidine resulted in demethylation of the DNMT3A gene, leading to restoration of its expression. Demethylation significantly potentiated the TRAIL-mediated apoptosis in PTC cells. Interestingly, silencing of DNMT3A using siRNA suppressed TRAIL-mediated apoptosis.
CONCLUSION
These findings suggest that DNMT3A alterations play an important role in PTC pathogenesis and demethylation agents can be used to restore the function of DNMT3A in a subset of patients with PTC.
Identifiants
pubmed: 31280122
pii: S0959-8049(19)30351-X
doi: 10.1016/j.ejca.2019.05.025
pii:
doi:
Substances chimiques
Biomarkers, Tumor
0
DNMT3A protein, human
0
DNA (Cytosine-5-)-Methyltransferases
EC 2.1.1.37
DNA Methyltransferase 3A
EC 2.1.1.37
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
133-144Informations de copyright
Copyright © 2019 Elsevier Ltd. All rights reserved.