A rigorous and comprehensive validation: common genetic variations and lung cancer.
BACKGROUND
Multiple recent genome-wide studies of single nucleotide polymorphisms (SNP) reported associations between candidate chromosome loci and lung cancer susceptibility. We evaluated five of the top candidate SNPs (rs402710, rs2736100, rs4324798, rs16969968, and rs8034191) for their effects on lung cancer risk and overall survival.


METHODS
Over 1,700 cases and 2,200 controls were included in this study. Seven independent, complementary case-control data sets were tested for risk assessment encompassing cigarette smokers and never smokers, using unrelated controls and unaffected full-sibling controls. Five patient groups were tested for survival prediction stratified by smoking status, histology subtype, and treatment.


RESULTS
After considering a history of chronic obstructive pulmonary disease as a risk factor altering lung cancer risk and comparing to sibling controls, none of the five SNPs remained significant. However, the variant rs4324798 was significant in predicting overall survival (hazard ratio, 0.46; 95% confidence interval, 0.30-0.73; P = 0.001) in small cell lung cancer.


CONCLUSIONS
None of the five candidate SNPs in lung cancer risk can be confirmed in our study. The previously reported association could be explained by disparity in tobacco smoke exposure and chronic obstructive pulmonary disease history between cases and controls. Instead, we found rs4324798 to be an independent predictor in small cell lung cancer survival, warranting further elucidation of the underlying mechanisms.
Yang
Ping
P
Department of 1Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. yang.ping@mayo.edu
Li
Yafei
Y
Jiang
Ruoxiang
R
Cunningham
Julie M
JM
Li
Yan
Y
Zhang
Fang
F
de Andrade
Mariza
M
D014408:Biomarkers, Tumor / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications; D012907:Smoking / Q000009:adverse effects
D014408:Biomarkers, Tumor