Efthymios Kyrodimos1, Aristeidis Chrysovergis1, Evangelos Tsiambas2, Vasileios S Papanikolaou1
11st ENT Department, Hippocration Hospital, University of Athens, Athens, Greece;
2Department of Pathology-Cytology, 401 GAH, Athens, Greece
Abstract
Dear Editor,
Microsatellites are referred to repetitive nucleotide sequences including usually 1 to 5 base pairs repeated for 15- 30 times which are normally relatively stable. Thousands of microsatellites are detectable throughout the human genome. In fact, during DNA replication accumulation of them forms a small loop in any of two strands. Insertion or deletion of these repeated nucleotide chains are identified also inside the introns of the genes. For all these molecular reasons, Microsatellite instability (MSI) is a biomarker for detecting DNA MMR deficiency in CRCs and also in a variety of malignancies of different histogenetic origin [1]. Among the genetic mechanisms that provide a stable micro-environment inside the molecule, DNA mismatch repair system (DNA MMR) plays a leading role. Humanized homologues of DNA MMR main genes are located on chromosomes 2, 3, 5 and 7 including MLH1, MSH2, MSH3, GTBP/MSH6, PMS1 and PMS2 [2]. Specific genomic alterations –germline mutations, accompanied usually by allelic loss (loss of heterozygosity -LOH), or epigenetic changes such as promoter hypermethylation- in the MMR genes lead to loss of their expression affecting their function in repairing the corresponding base to base errors. In contrast to colon adenocarcinoma, there are limited data regarding DNA MMR and MSI in oral cavity carcinomas. Two independent study groups were based on patients with different ethnicity (Korean vs Asian Indians) exploring specific genetic polymorphism of the hMLH1gene. They reported that hypermethylation of the hMLH1 gene may be the principal inactivating mechanism in oral cancer with MSI in HPV related lesions and also that the hMLH1 -93 A>G polymorphism is associated with the higher risk of tobacco-related OSCC could be useful in screening population at a higher risk [3,4]. Hypermethylation of hMLH1 and hMSH2 might play a role in oral carcinogenesis and may be correlated with a tendency to develop multiple oral malignancies. Furthermore, expression of hMLH1, hPMS2, and hMSH2 genes seem to be related progressively with oral epithelial dysplasia and squamous cell carcinoma. Immunohistochemical analyses showed that reduced expression of these markers was correlated with dysplasia to carcinoma progression and also with the grade of the carcinomas (poorly differentiated from well-differentiated) [5]. Identification of specific gene deregulation mechanisms regarding DNA MMR genes is a significant issue for understanding their altered protein expression. Reduced expression levels of these markers are correlated with MSI both in oral cavity carcinomas. hMLH1 is a crucial gene for both of them and its abnormal expression and function influences the progression and the biological behavior in these malignancies.
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