These findings suggest FHIT methylation is associated with a higher susceptibility and has a prognostic significance in early stage lung cancer in the Han population of southern-central China and may represent a marker for progressive disease.
The coincidence of a chromosomal fragile site, FRA3B, at a common chromosomal breakpoint in lung cancer has suggested that fragility at this site may predispose to breakage that could contribute to multistep carcinogenesis.
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.
To avoid overlooking tumor-specific altered transcripts due to contaminating normal cells in primary tumors, FHIT alterations were examined in 41 lung cancer cell lines in the present study.
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.
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.
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.
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.