To assess the frequency and specificity of inactivation and its relevance in a clinical setting, we have produced antibodies against the Fhit protein and studied its expression in a series of non-small cell lung cancers and normal bronchial mucosa and a spectrum of preinvasive lesions by immunohistochemistry.
Our findings support the conclusion that FHIT/FRA3B abnormalities are associated with lung cancer pathogenesis but that FHIT abnormalities differ from the types of mutations and lack of wild-type transcript found in classic tumor suppressor genes, and functional studies are needed to define the role of FHIT in thoracic tumorigenesis.
In this report, we describe an improved extruded DOTAP:cholesterol (DOTAP:Chol) cationic liposome that efficiently delivers therapeutic tumor suppressor genes p53 and FHIT, which are frequently altered in lung cancer, to localized human primary lung cancers and to experimental disseminated metastases.
Small cell lung tumors (80%) and non-small cell lung cancers (40%) showed abnormalities in RNA transcripts of FHIT, and 76% of the tumors exhibited loss of FHIT alleles.
Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in <i>RGL1:RAD51B</i> (OR=0.44, <i>p</i> value=3.27x10<sup>-11</sup> in overall lung cancer and OR=0.41, <i>p</i> value=9.71x10<sup>-11</sup> in non-small cell lung cancer), <i>SYNE1:RNF43</i> (OR=0.73, <i>p</i> value=1.01x10<sup>-12</sup> in adenocarcinoma) and <i>FHIT:TSPAN8</i> (OR=1.82, <i>p</i> value=7.62x10<sup>-11</sup> in squamous cell carcinoma) in our analysis.
The aim of this study was to identify FHIT gene alterations in bronchoscopy specimens of patients with suspected lung cancer and to determine the molecular relevance, if any, of FHIT alterations in the development of cancer.
These results indicate that the tumour suppressor properties of Fhit are strictly related to its expression level and show that the Fhit protein has a dose-dependent antiproliferative effect on the Fhit-negative Calu-1 lung cancer cell line.
We examined aberrant expression of the Fhit protein and allele loss at the FHIT gene in a series of lung cancer cases, mainly of non-small cell carcinoma (NSCLC) histology.
Detecting FHIT deletions for lung cancer diagnosis produced 58% sensitivity in the enriched sputum, whereas there was 42% sensitivity in the unenriched samples (P = .02).
All of these findings are consistent with loss of Fhit protein expression being as frequent an abnormality in lung cancer pathogenesis as are p53 and p16 protein abnormalities and that such loss occurs independently of the commitment to the metastatic state and of most other molecular abnormalities.
Normal FHIT transcripts in renal cell cancer- and lung cancer-derived cell lines, including a cell line with a homozygous deletion in the FRA3B region.
These results suggest that the high methylation statuses of p16, RASSF1A, or FHIT genes were associated with a significantly increased risk of lung cancer; the risk of lung cancer increased as the methylation status increased.
LOH of the FHIT locus was frequently found among the lesions of hyperplasia and atypical hyperplasia obtained from 6 patients with a 1- to 36-year history of PT (12 of 30 informative lesions, 40%); none of 70 hyperplastic lesions obtained from 14 patients with a 1- to 11-month history of PT showed LOH at the FHIT gene; 17 of 20 (85%) cancer lesions obtained from 20 lung cancer patients with a 2- to 53-year history of previous PT showed LOH at the FHIT gene, which was significantly higher than hyperplasia and atypical hyperplasia obtained from patients with a 1- to 36-year history of PT in FHIT LOH (Fisher's exact test p = 0.003).