PURPOSE: The Int6 gene was originally identified as a common insertion site for 
the mouse mammary tumor virus in virally induced mouse mammary tumors. Recent 
studies indicate that Int6 is a multifaceted protein involved in the regulation 
of protein translation and degradation through binding with three complexes: the 
eukaryotic translation initiation factor 3, the proteasome regulatory lid, and 
the constitutive photomorphogenesis 9 signalosome. This study aimed to 
investigate the prognostic role of Int6 in a large series of stage I non-small 
cell lung cancers (NSCLC) patients with long-term follow-up.
EXPERIMENTAL DESIGN: We determined the methylation status of Int6 DNA by 
methylation-specific PCR and the steady-state levels of Int6 RNA by quantitative 
real-time reverse transcription-PCR in 101 NSCLCs and matched normal lung 
tissues.
RESULTS: In 27% of the tumors, Int6 RNA levels were reduced relative to normal 
tissue. In 85% of the tumors with reduced Int6 expression, the transcription 
promoter and first exon were hypermethylated, whereas only 4% of the tumors with 
elevated Int6 RNA levels were hypermethylated (P <0.000001). Low levels of Int6 
RNA were found a significant predictor of overall and disease-free survival 
(P=0.0004 and P=0.0020, respectively). A multivariate analysis confirmed that 
low Int6 expression was the only independent factor to predict poor prognosis, 
for both overall (P=0.0006) and disease-free (P=0.024) survival.
CONCLUSIONS: Our results suggest that Int6 expression, evaluated by quantitative 
real-time PCR, may represent a new prognostic factor in patients with stage I 
NSCLC.