| Abstract |
Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic interstitial pneumonia limited to the lung and characterized by a fibroproliferative response with only minor signs of inflammation, which almost always causes rapid fibrotic destruction of the lung. Recently, we reported that genetic alterations at the microsatellite level are frequent in this disease. In this study, we used 40 microsatellite DNA primers, approximately half of them located on regions frequently deleted in lung cancer. We analyzed, using multiplex PCR-based microsatellite assays, 26 sputum specimens from IPF patients and 26 from healthy matched subjects, versus correspondent venous blood. Loss of heterozygosity (LOH) was found in ten (38.5%) patients in at least one locus, while none of the healthy subjects exhibited any genetic alteration in the studied markers. The majority of these alterations (81.8%) were found on markers previously associated with lung cancer located on 1p34.3, 3p21.32-p21.1, 5q32-q33.1, 9p21 and 17p13.1 where MYCL1, hMLH1, SPARC, p16Ink4 and TP53 genes have been mapped. These data provide new insights on IPF pathogenesis as well as a new perspective for its correlation with lung cancer. On the other hand, pulmonary sarcoidosis shares certain features with immune disease and neoplasia, and microsatellite DNA alterations are detectable in sputum specimens of pulmonary sarcoidosis patients. The biological basis and significance of these findings remain obscure, while information regarding the genetic basis of the disease is limited. Using multiplex PCR-based microsatellite analysis, we investigated 40 markers located on 1p, 1q, 2p, 2q, 3p, 5q, 6p, 7p, 9p, 11q, 14q and 17p in 38 sputum specimens of pulmonary sarcoidosis patients. Loss of heterozygosity (LOH) was found in 13 of 38 (34.2%) patients in at least one locus. These alterations occurred in the subset of markers located in or close to DNA mismatch repair (MMR) genes, hMSH2 (2p22.3-p16.1) and hMLH1 (3p21.32-p21.1), as well as in CD48 (1q21-q23) and IRF4 (6p23-p25) genes associated with lymphocyte activation. Microsatellite instability (MIN) was observed in five cases (13.2%) in at least one locus. Our data suggest that genomic instability in pulmonary sarcoidosis could be due to MMR defects, while alterations of lymphocyte-specific agents could account for granuloma formation.
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Ανίχνευση μεταλλάξεων στα γονίδια επιδιόρθωσης του DNA σε ασθενείς με σαρκοείδωση και ιδιοπαθή πνευμονική ίνωση
