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.
Highlights
Gene silencing of the repair genes Mut-L Homologue 1 (MLH1) and methylguanine DNA methyltransferase (MGMT) was shown to be a mechanism underlying the development of microsatellite instability (MSI), a phenotype frequently associated with various human malignancies
As most IDH1 and RAS mutations found in our series of thyroid carcinomas were transitions [12] and considering that an association between MGMT and transitions exists, we assessed whether the presence of IDH1 and RAS mutations is associated with MGMT methylation and/or loss of MGMT expression
No BRAF V600E mutations were found in the 12 Follicular Thyroid Carcinoma (FTC) samples (0%)
Summary
Gene 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. 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. Papillary Thyroid Carcinoma (PTC) is the most common subtype, representing approximately 80% of cases. Mutations in RET/PTC, RAS, or BRAF, which result in constitutive MAPK signalling, are found in approximately 70% of PTC cases with little overlap between mutated genes. BRAF V600E is the most common genetic alteration found in PTC, with a worldwide prevalence of 29 to 83% [5,6,7,8,9]. RET/PTC rearrangements are the second most common genetic alteration found in PTC. The PI3K pathway can be activated through acquisition of RAS or PAX8/ PPAR gamma mutations
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