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Int6 Expression Can Predict Survival in Early-Stage Non–Small Cell Lung Cancer Patients

Authors' Affiliations: ¹ Clinical Research Center, Center of Excellence on Aging, University Foundation, Chieti, Italy; ² Department of Surgery, University of Pisa, Pisa, Italy; ³ Department of Surgery, University of Chieti, Chieti, Italy; and ⁴ Oncogenetic Section, Mammary Biology and Tumorigenesis Laboratory, National Cancer Institute, NIH, Bethesda, Maryland

Requests for reprints: Antonio Marchetti, Pathology Unit, Clinical Research Center, Center of Excellence on Aging, University Foundation, Via Colle Dell'Ara, 66013 Chieti, Italy. Phone: 39-871-357407, ext. 408; Fax: 39-871-540079; E-mail: amarchetti{at}unich.it.

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.

Key Words: eIF3 • Proteasome • methylation • real-time PCR • prognostic factors

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