Originally published as JCO Early Release 10.1200/JCO.2008.18.7906 on May 4 2009

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Genome-Wide Analysis of Survival in Early-Stage Non–Small-Cell Lung Cancer

From the Department of Epidemiology, Department of Biostatistics and Department of Environmental Health, Harvard School of Public Health; the Department of Pathology, Brigham and Women's Hospital; and the Cancer Center and the Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, MA; and the Section of Toxicology, Department of Biological and Chemical Working Environment, National Institute of Occupational Health, Oslo, Norway.

Corresponding author: David C. Christiani, MD, MPH, Department of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Boston, MA 02115; e-mail: dchris{at}hsph.harvard.edu.

Purpose Lung cancer, of which 85% is non–small-cell (NSCLC), is the leading cause of cancer-related death in the United States. We used genome-wide analysis of tumor tissue to investigate whether single nucleotide polymorphisms (SNPs) in tumors are prognostic factors in early-stage NSCLC.

Patients and Methods One hundred early-stage NSCLC patients from Massachusetts General Hospital (MGH) were used as a discovery set and 89 NSCLC patients collected by the National Institute of Occupational Health, Norway, were used as a validation set. DNA was extracted from flash-frozen lung tissue with at least 70% tumor cellularity. Genome-wide genotyping was done using the high-density SNP chip. Copy numbers were inferred using median smoothing after intensity normalization. Cox models were used to screen and validate significant SNPs associated with the overall survival.

Results Copy number gains in chromosomes 3q, 5p, and 8q were observed in both MGH and Norwegian cohorts. The top 50 SNPs associated with overall survival in the MGH cohort (P 2.5 x 10^–4) were selected and examined using the Norwegian cohort. Five of the top 50 SNPs were validated in the Norwegian cohort with false discovery rate lower than 0.05 (P < .016) and all five were located in known genes: STK39, PCDH7, A2BP1, and EYA2. The numbers of risk alleles of the five SNPs showed a cumulative effect on overall survival (P_trend = 3.80 x 10^–12 and 2.48 x 10^–7 for MGH and Norwegian cohorts, respectively).

Conclusion Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC.

Supported by Grants No. CA092824 (D.C.C.), CA074386 (D.C.C.), and CA090578 (D.C.C.) and funding (X.L.) from the National Institutes of Health; and the Norwegian Cancer Society (V.S., A.H.).

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

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