Originally published as JCO Early Release 10.1200/JCO.2005.04.4339 on March 20 2006

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Association of the PDCD5 Locus With Lung Cancer Risk and Prognosis in Smokers

Monica Spinola, Peter Meyer, Stefan Kammerer, F. Stefania Falvella, Melanie B. Boettger, Carolyn R. Hoyal, Carmen Pignatiello, Reiner Fischer, Richard B. Roth, Ugo Pastorino, Karl Haeussinger, Matthew R. Nelson, Rainer Dierkesmann, Tommaso A. Dragani, Andreas Braun

From the Department of Experimental Oncology and Laboratories, Thoracic Surgery, Istituto Nazionale Tumori, Milan, Italy; Asklepios Clinics, Pneumology Clinic, Munich-Gauting; Genefinder Technologies Ltd, Munich; Institute of Human Genetics, Molecular Oncogenetics Division, University Hospital, Tuebingen; Clinic Schillerhoehe, Pneumology Clinic, Stuttgart-Gerlingen, Germany; and Sequenom Inc, San Diego, CA.

Address reprint requests to Tommaso A. Dragani, PhD, Department of Experimental Oncology, Istituto Nazionale Tumori, Via G. Venezian 1, 20133 Milan, Italy; e-mail: tommaso.dragani{at}istitutotumori.mi.it

PURPOSE: Whole-genome scan association analysis was carried out to identify genetic variants predictive of lung cancer risk in smokers and to confirm the identified variants in an independent sample.

PATIENTS AND METHODS: A case-control study was performed using two pools consisting of DNA from 322 German smoking lung cancer patients and 273 healthy smoking controls, respectively. A replication study was carried out using 254 Italian lung adenocarcinoma (ADCA) patients and 235 healthy controls.

RESULTS: Patients with genotypes GG or CG for the rs1862214 single nucleotide polymorphism, 5' upstream of the programmed cell death 5 (PDCD5) gene, compared with those with the common genotype CC showed an increased risk of lung cancer (odds ratio, 1.6; 95% CI, 1.2 to 2.1) and a higher incidence of poor clinical stage disease (hazard ratio [HR], 1.9; 95% CI, 1.1 to 3.4; P = .023), nodal involvement (HR, 1.9; 95% CI, 1.1 to 3.6; P = .033), and short-term survivorship (HR, 1.8; 95% CI, 1.2 to 2.6, P = .003). PDCD5 mRNA expression levels were approximately 2.4-fold lower in lung ADCA as compared to normal lung tissue. Human NCI-H520 cancer cells transfected with PDCD5 cDNA showed decreased colony-forming ability.

CONCLUSION: These results suggest that the rs1862214 polymorphism in PDCD5 is predictive for lung cancer risk and prognosis, and that PDCD5 may represent a novel tumor suppressor gene influencing lung cancer.

Supported in part by grants from Associazione and Fondazione Italiana Ricerca Cancro (AIRC and FIRC) and Fondo Investimenti Ricerca de Base (FIRB) to T.A.D.

M.S., P.M., and S.K. contributed equally to this manuscript. R.D., T.A.D., and A.B. contributed equally to this manuscript.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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