Genome-wide analysis of survival in early-stage non-small-cell lung cancer.
OBJECTIVE
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.


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 < or = 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).


CONCLUSIONS
Five SNPs were identified that may be prognostic of overall survival in early-stage NSCLC.
Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
Yen-Tsung
YT
Huang
Rebecca S
RS
Heist
Lucian R
LR
Chirieac
Xihong
X
Lin
Vidar
V
Skaug
Shanbeh
S
Zienolddiny
Aage
A
Haugen
Michael C
MC
Wu
Zhaoxi
Z
Wang
Li
L
Su
Kofi
K
Asomaning
David C
DC
Christiani
D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D015820:Cadherins / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D002893:Chromosomes, Human, Pair 3; D002895:Chromosomes, Human, Pair 5; D002898:Chromosomes, Human, Pair 8; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D009367:Neoplasm Staging; D009664:Norway / Q000453:epidemiology; D009687:Nuclear Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D020641:Polymorphism, Single Nucleotide; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D017027:Protein Tyrosine Phosphatases / Q000235:genetics; D000091363:Protocadherins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics; D015203:Reproducibility of Results; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors
D014408:Biomarkers, Tumor; D015820:Cadherins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; C113391:PCDH7 protein, human; D000091363:Protocadherins; C455479:RBFOX1 protein, human; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; C486409:STK39 protein, human; C106938:EYA2 protein, human; D017027:Protein Tyrosine Phosphatases