Correlation of MLH1 and MGMTexpression and promoter methylation with genomic instability in patients with thyroid carcinoma

Abstract

BackgroundGene silencing of the repair genes MLH1 and MGMT was shown to be a mechanism underlying the development of microsatellite instability (MSI), a phenotype frequently associated with various human malignancies. Recently, aberrant methylation of MLH1, MGMT and MSI were shown to be associated with mutations in genes such as BRAF, RAS and IDH1 in colon and brain tumours. Little is known about the methylation status of MLH1 and MGMT in thyroid tumours and its association with MSI and mutational status.MethodsIn a series of 96 thyroid tumours whose mutational profiles of BRAF, IDH1 and NRAS mutations and RET/PTC were previously determined, we investigated MLH1 and MGMT expression and methylation status by qPCR and methylation-specific PCR after bisulphite treatment, respectively. MSI was determined by PCR using seven standard microsatellite markers.ResultsSamples with point mutations (BRAF, IDH1 and NRAS) show a decrease in MLH1 expression when compared to negative samples. Additionally, malignant lesions show a higher MSI pattern than benign lesions. The MSI phenotype was also associated with down-regulation of MLH1.ConclusionsThe results of this study allow us to conclude that low expression of MLH1 is associated with BRAF V600E mutations, RET/PTC rearrangements and transitions (IDH1 and NRAS) in patients with thyroid carcinoma. In addition, a significant relationship between MSI status and histological subtypes was found.

Research Progress of DNA Methylation in Thyroid Cancer

“…A study indicated that abnormal methylation of MLH1 was significantly correlated with lymph node metastasis of PTC, suggesting that MLH1 might be a molecular marker of lymph node metastasis in PTC [34]. Another study found that there were abnormal methylation and low expression of MLH1 in thyroid cancer and MLH1 expression is associated with BRAF, IDH1, and NRAS gene mutations [35].…”

EGCG Containing Combined Dietary Supplement Affects Telomeres and Epigenetic Regulation

“…In addition, Fang et al demonstrated that EGCG in vitro caused a reversal of hypermethylation of retinoic acid receptor beta (RARbeta), p16 (INK4a), O(6)-methylguanine methyltransferase (MGMT), and human mutL homologue 1 (hMLH1) genes in cancer cells with a concurrent effect on the expression of mRNA of these genes [42]. Gene silencing and promoter methylation of mismatch repair (MMR) genes MLH1 and MGMT was shown to be associated to the development of microsatellite instability (MSI) which itself is involved with various human malignancies like cancer [47]. Furthermore, MMR proteins were reported to interact with silencing epigenetic modifiers such as DNMTs when damages exceed the repair capacity [48].…”

Overview of Hurthle cell carcinoma of thyroid

“…IDH1, isocitrate dehydrogenase 1 [34,35] Produces 2-hydroxyglutarate (2HG), which induces histone-and DNA-hypermethylation through inhibition of epigenetic regulators GNAS, guanine nucleotide stimulatory protein [36] encodes the alpha subunit of the stimulatory G protein. Activating mutation of the alpha subunit of the GNAS gene results in activation of adenylyl cyclase for cell division.…”