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Identifier uch.med.phd//2000vasilakis
Title Μελέτη της αστάθειας μικροδορυφορικού DNA σε κυτταρολογικά δείγματα ασθενών με διάμεση διηθητική πνευμονοπάθεια
Creator Vasilakis, Dimitris A
Abstract The Diffuse Interstitial Lung Diseases (DILD), are a heterogeneous group of diseases of the lung, which are characterized by disorganization of the alveolar walls and decline in the number of the functional units of the lung parenchyma. Based on new biological data, it is obvious that common factors exist in the aitiopathogenesis of these disorders. A common finding in all DILD is, for example, the non-specific alveolitis; very little is though known on the molecular basis of these diseases. On the other hand, for the Idiopathic Pulmonary Fibrosis (IPF) it was observed since 1965, that a higher incidence of lung cancer exists for these patients. Why this is happening remains obscure, as well as the molecular basis of these diseases. Instability of tandem repeat DNA sequences or Microsatellite Instability (MSI), which is a genetic alteration of neoplasmatic cells, has been correlated with high mutational rate, and DNA repair processes. MSI has been found in various cancers, including lung. Additional information on the molecular pathway of cancer development is provided by the identification of novel tumor suppressor genes (TSGs). The inactivation of TSGs plays a critical role in multistage carcinogenesis. At present, loss of heterozygosity (LOH) using highly polymorphic microsatellite markers is the most common methodology employed for the localization of sites in the genome with high probability for the presence of candidate TSGs. Until today the above mentioned genetic alterations were not studied in patients with DILD. The present protocol was designed to study the genetic alterations at the microsatellite level, in blood and sputum cytological specimens from patients with DILD, which could be part of the complex genetic basis of these diseases. To the best of our knowledge this is the first genetic study in micrsatellite level in patients with DILD. We studied sputum cells from patients with sarcoidosis and IPF, were we detected MSI or LOH. The two studied diseases were selected as representative DILD disorders, since sarcoidosis is a systematic disease of mild progress and intermediate probability for developing lung cancer and IPF being a progressive disease with a high probability of developing lung cancer. We also examined the possible use of MSI and LOH as a marker of severity for the two diseases. We studied sputum cytological specimens from 30 patients with sarcoidosis and 26 patients with IPF, using 10 highly polymorphic microsatellite markers located in several chromosomal arms. The electrophoretic pattern of each specimen was compared with the corresponding pattern of peripheral blood and any difference in the mobility of the microsatellite alleles was interpreted as MSI positive. LOH was scored as decreases in intensity (at least 50%), of one allele relative to the other as determined from comparison of sputum and normal DNAs. Our results showed that 14 (47%) sarcoidosis patients and 13 (50%) of the IPF patients, showed genetic alterations, either MSI or LOH. Six (20%) sarcoidosis patients and 5 (19%) IPF patients, exhibited MSI in at least one microsatellite marker. Nine (30%) of the sarcoidosis patients and 10 (38%) of the IPF patients, exhibited LOH in at least one marker. One of the sarcoidosis patients showed complete deletion of chromosomal arm 17q11.2-q21. No correlation was found between the genetic alterations studied and age, duration of illness, blood gases or spirometry parameters of the patients. Conclusion: MSI is frequently observed in sarcoidosis and IPF and seems not related with the severity of the disease. LOH incidence indicates the presence of putative tumor-suppressor genes at loci examined, which may play an important role in the aetiopathogenesis of these entities.
Issue date 2000-04-01
Date available 2000-07-24
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
Permanent Link https://elocus.lib.uoc.gr//dlib/c/5/2/metadata-dlib-2000vasilakis.tkl Bookmark and Share
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