Author:
Santos Juliana Carvalho,Bastos André Uchimura,Cerutti Janete Maria,Ribeiro Marcelo Lima
Abstract
Abstract
Background
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. 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.
Methods
In 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.
Results
Samples 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.
Conclusions
The 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.
Publisher
Springer Science and Business Media LLC
Subject
Cancer Research,Genetics,Oncology
Reference29 articles.
1. SEER Cancer Statistics Review. Edited by: Horner MJ, Ries LAG, Krapcho M, Neyman N, Aminou R, Howlader N, Altekruse SF, Feuer EJ, Huang L, Mariotto A, Miller BA, Lewis DR, Eisner MP, Stinchcomb DG, Edwards BK. 1975, Bethesda, MD: National Cancer Institute, -2006
2. Mingzhao X: Recent advances in molecular biology of thyroid cancer and their clinical implications. Otolaryngol Clin North Am. 2008, 41: 1135-1146. 10.1016/j.otc.2008.07.001.
3. Kohno M, Pouyssegur J: Targeting the ERK signaling pathway in cancer therapy. Ann Med. 2006, 38: 200-211. 10.1080/07853890600551037.
4. Kondo T, Ezzat S, Asa SL: Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer. 2006, 6: 292-306. 10.1038/nrc1836.
5. Ciampi R, Nikiforov YE: Minireview: RET/PTC Rearrangements and BRAF Mutations in Thyroid Tumorigenesis. Endocrinology. 2007, 148: 936-941. 937