Lung tumours from non-smoking subjects: A p53-related genetic instability in a subset of cases.
Tumours developed in non-smoking patients represent about 10% of all lung neoplasms and show peculiar morphologic and genetic features. In a previous study, we found a constant association between p53 gene alterations and loss of heterozygosity (LOH) at the FHIT locus in a subset of non-smoking tumours (7 cases out of 35 analyzed), so we hypothesized that a genomic instability associated with p53 mutations could be the cause of FHIT LOH in these neoplasms. To test this hypothesis, in the same panel of tumours, we investigated the presence of LOH at 7 other microsatellite loci located on different chromosomes. Interestingly we found that all of the tumours with p53 alterations and LOH at the FHIT locus showed loss of heterozygosity at all of the informative tested loci. This association was statistically significant (p=0.0001). Our data indicate the presence of a generalized genomic instability in this subset of lung tumours. Since p53 alterations were mostly G:C --> A:T transitions and frameshift deletions, we are tempted to hypothesize that the genomic instability observed in non-smoking patients could be caused by particular p53 alterations. In fact, other kind of p53 mutations (G:C --> T:A transversions), frequently found in a series of 35 tumours of smokers used as control, were not associated with LOH at microsatellites loci. However, we cannot exclude that p53 alterations are a consequence and not the cause of the genomic instability. In this case, we have to admit that a gene(s), upstream of p53, is implicated in genome destabilisation in a subset of lung adenocarcinomas developed in non-smoking patients.
Pellegrini
S
S
Department of Experimental Pathology, Medical Biotechnology, Epidemiology and Infettivology, University of Pisa, Pisa, Italy.
Bertacca
G
G
Buttitta
F
F
Bevilacqua
G
G
Marchetti
A
A
D005260:Female; D016158:Genes, p53; D020022:Genetic Predisposition to Disease; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D012907:Smoking