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Three-Gene Expression Signature Predicts Survival in Early-Stage Squamous Cell Carcinoma of the Lung

Authors' Affiliations: ¹ University of Gdansk, Gdansk, Poland; ² Catalan Institute of Oncology, Badalona, Spain; ³ Autonomous University of Madrid and ⁴ Hospital Puerta de Hierro, Madrid, Spain; ⁵ University of California, San Francisco, California; and ⁶ Hospital General de Alicante, Alicante, Spain

Requests for reprints: Rafael Rosell, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Ctra Canyet, s/n, 08916 Badalona, Barcelona, Spain. Phone: 34-93-497-89-25; Fax: 34-93-497-89-50; E-mail: rrosell{at}ico.scs.es.

Purpose: Adjuvant treatment may improve survival in early-stage squamous cell carcinoma (SCC) of the lung; however, the absolute gain is modest and mainly limited to stage II-IIIA. Current staging methods are imprecise indications of prognosis, but high-risk patients can be identified by gene expression profiling and considered for adjuvant therapy.

Experimental Design: The expression of 29 genes was assessed by reverse transcriptase quantitative PCR in frozen primary tumor specimens obtained from 66 SCC patients who had undergone surgical resection. Expression values were dichotomized using the median as a cutoff value. We used a risk score to develop a gene expression model for the prediction of survival.

Results: The univariate analysis of gene expression in the training cohort identified 10 genes with significant prognostic value: CSF1, EGFR, CA IX, PH4, KIAA0974, ANLN, VEGFC, NTRK1, FN1, and INR1. In the multivariate Cox model, CSF1 (hazard ratio, 3.5; P = 0.005), EGFR (hazard ratio, 2.7; P = 0.02), CA IX (hazard ratio, 0.2; P < 0.0001), and tumor size >4 cm (hazard ratio, 2.7; P = 0.02) emerged as significant markers for survival. The high prognostic value of a risk score based on the expression of the three genes (CSF1, EGFR, and CA IX) was positively validated in a separate cohort of 26 patients in an independent laboratory (P = 0.05).

Conclusions: The three-gene signature is strongly associated with prognosis in early-stage SCC. Positive independent validation suggests its suitability for selecting SCC patients with an increased risk of death who might benefit from adjuvant treatment.