| Abstract |
Several lines of evidence provide two hypotheses in the effort to identify the pathogenesis of the disease. Some studies, using genetic polymorphisms and linkage analysis, implicate genes which encode for metabolic and detoxification enzymes, such as galactose 1-phosphate uridyl tranferase (GALT) located on 9p21 and glutathione S-transferase M1 (GSTM1) located on 1p13 respectively, to the pathogenesis of the disease. The second hypothesis proposes endometriosis as a disorder with cancer predispositional characteristics. Although, endometriosis is considered to be a benign condition, it is sometimes found in close association with ovarian carcinoma, particularly endometrioid and clear cell subtypes, suggesting malignant progression. Moreover, the glandular epithelium of endometriosis can show cytological atypia, and there is evidence that DNA aneuploidy and loss of heterozygosity occur. These studies demonstrate tumor suppressor genes as crucial factors for the development of endometriosis. Thus, the above hypothesies indicate endometriosis, as a complex trait, in which multiple gene loci, with different functions, interact with each other and the environment, from different pathways to produce the disease phenotype. Additionally, an array of DNA repair systems function in the cell, in order to avoid the effects of accumulation of DNA alterations. The DNA mismatch repair system (MMR), plays a crucial role in this process by counteracting effects caused by DNA damage, genetic recombination or replication errors. In human, two different heterodimeric complexes of MutS-related proteins (hMSH2-hMSH3 and hMSH2-hMSH6) and two different heterodimeric complexes of MutL-related proteins (hMLH1-hPMS2 and hMLH1-hPMS1) have been characterized as fundamentals for the proper function of MMR, in both base and insertion/deletion mispairing. In this context, we have used PCR-based microsatellite DNA analysis to investigate the probability of allelic imbalance (also termed loss of heterozygosity, LOH) in candidate susceptibility genetic loci to endometriosis. Although the detection of an allelic imbalance can not support alone a full gene inactivation hypothesis, it is a direct indication of genomic instability. The frequency of its occurrence in a specific chromosomal region in concordance with a specific phenotype may have a functional significance. Adenomyosis is a gynecological condition in which tissue histologically similar to that in endometrium is found within the endometrium in the uterus. Although, lesions of both adenomyosis and endometriosis are identical to their sources with respect to structure and function, they are generally regarded as separate and distinct nosologic processes. In this study we used 17 microsatellite markers in four tetraplex and one single PCR assay, to determine the incidence of loss of heterozygocity (LOH) in 31 cases of adenomyosis. The markers used are located close to tumor suppressor genes, DNA repair genes, and genes which are thought to be involved in endometriosis. Moreover, the markers were involved in regions frequently lost in ovarian cancer, on chromosomal arms 1p, 1q, 2p, 2q, 3p, 9p, 9q, 17p and 17q. Nine samples (29.0%) showed LOH in at least one locus. Loci 2p22.3 ? p16.1, 3p24.2-p22 and 9p21 exhibited imbalance (19.4%, 9.7% and 6.5% respectively). This is the first report, that LOH occurs in adenomyosis. The regional chromosomal losses were detectable early during the development of this condition. In addition, hMSH2, hMLH1, p16Ink4 and GALT genes were associated for the first time with adenomyosis and its pathogenesis.
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Αστάθεια μικροδορυφορικού DNA στην ενδομητρίωση και αδενομύωση
