In order to identify a possible hereditary predisposition to the development of obstructive pulmonary disease of unknown origin, we have looked for the presence of Cystic Fibrosis Transmembrane Regulator (CFTR) gene mutations in unrelated patients with no signs of Cystic Fibrosis (CF). We screened for 70 common mutations, and also for rare mutations by denaturing gradient gel electrophoresis analysis. In this search, different CFTR gene mutations (R75Q, delta F508, R1066C, M1137V and 3667ins4) were found in five out of 16 adult Italian patients with disseminated bronchiectasis, a significant increase over the expected frequency of carriers. Moreover, three rare CFTR gene DNA polymorphisms (G576A, R668C, and 2736 A-->G), not deemed to be the cause of CF, were found in two patients, one of which was a compound heterozygote with R1066C. These results indicate that CFTR gene mutations, and perhaps also DNA polymorphisms, may be involved in the etiopathogenesis of at least some cases of bronchiectasis.

In order to determine the possible role of the cystic fibrosis transmembrane regulator (CFTR) gene in pulmonary diseases not due to cystic fibrosis, a complete screening of the CFTR gene was performed in 120 Italian patients with disseminated bronchiectasis of unknown cause (DBE), chronic bronchitis (CB), pulmonary emphysema (E), lung cancer (LC), sarcoidosis (S) and other forms of pulmonary disease. The 27 exons of the CFTR gene and their intronic flanking regions were analyzed by denaturing gradient gel electrophoresis and automatic sequencing. Mutations were detected in 11/23 DBE (P = 0.009), 7/25 E, 5/27 CB, 5/26 LC, 5/8 S (P = 0.013), 1/4 tuberculosis, and 1/5 pneumonia patients, and in 5/33 controls. Moreover, the IVS8-5T allele was detected in 6/25 E patients (P = 0.038). Four new mutations were identified: D651N, 2377C/T, E826K, and P1072L. These results confirm the involvement of the CFTR gene in disseminated bronchiectasis of unknown origin, and suggest a possible role for CFTR gene mutations in sarcoidosis, and for the 5T allele in pulmonary emphysema.

Obstructive pulmonary disease is a multifactorial condition deriving from the interaction of environmental and genetic factors. From biochemical knowledge of the basis of the disease, alpha 1-antitrypsin and alpha 1-antichymotrypsin are considered two likely candidate genes. We therefore designed an association study comprising 232 unrelated Italian individuals divided as follows: 89 individuals with obstructive lung disease (66 with COPD and 23 with disseminated bronchiectasis) and 143 controls (45 patients with non-obstructive lung disease and 98 healthy individuals). We screened for Taq I (G1237A) polymorphism of the alpha 1-antitrypsin gene as well as the rare variants Bonn-1 (Pro229Ala), Bochum-1 (Leu55Pro), Isehara-1 (Met389Val) and Isehara-2 (1258delAA), and the common signal peptide polymorphism Thr-15Ala of the alpha 1-antichymotrypsin gene. The frequencies of Taq I G1237A alleles were 11.7 and 10.8% in obstructed patients and controls, respectively (P = 0.43), while those of signal peptide Thr-15Ala alleles were 51.6 and 50.3% in obstructed patients and controls, respectively (P = 0.42). We conclude that alpha 1-antitrypsin Taq I polymorphism and alpha 1-antichymotrypsin Thr-15Ala mutation are not major genetic risk factors for the development of obstructive lung disease in Italian patients. The alpha 1-antichymotrypsin rare variants were not detected: our results do not exclude the possibility that other alpha 1-antichymotrypsin gene mutations might be present in Italian obstructed patients but, if so, these genetic defects must be rare.

Cancer results from the expansion of cell clones that progressively lose control of proliferation, differentiation, and death, owing to accumulation of mutational events in genes that control the cell cycle and apoptosis. Nuclear protein p53 is thought to play a major role in malignancy, since it induces genes that determine apoptosis and cell-cycle arrest, interacts with proteins employed in DNA repair, and binds to DNA strand breaks. As expected, somatic mutations in p53 are found in a variety of human cancers. Mutations are predominantly inactivating, thus eliminating the "guardian of the genome" from the proliferating cells. Germ-line mutations