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Objective: To investigate the effect of a common polymorphism rs928508(A/G) in flanking region of miR-30c on the expression of pri, pre and mature miR-30c, and discuss the effect of this polymorphism on the maturing process of miR-30c in lung carcinoma., Methods: The pGL3-promoter-miR-30c-A and pGL3-promoter-miR-30c-G luciferase plasmids were created containing A or G allele of miR-30c flanking region. Taqman assay was used to genotype rs928508 polymorphism in 50 lung cancer tissues. RT-PCR was performed to determine the expression of pri-miR-30c, pre-miR-30c, mature miR-30c and miR-30c host gene NFYC in the 50 lung cancer tissues., Results: The luciferase expression level of the pGL3-promoter-miR-30c-A construct group was not significantly different compared with that in the the pGL3-promoter-miR-30c-G construct group (A549 cells, P = 0.758; 293A cells, P = 0.554; CHO cells, P = 0.175). The results demonstrated that rs928508(A/G) variant had no effect on the transcriptional regulation of pri-miR-30c. In the genotype-phenotype collection analysis of the 50 lung cancer tissues, the expression of pre-miR-30c and mature miR-30c for rs928508 AG/GG genotypes showed significantly lower levels compared with those in the AA genotype (P = 0.009, P = 0.011). However, the expression of pri-miR-30c showed no significant difference between AG/GG genotypes and AA genotype. Similarly, the expression of host NFYC gene was correlated with pri-miR-30c, showed no significant difference between AG/GG genotypes and AA genotype., Conclusion: The rs928508(A/G) polymorphism in flanking region of miR-30c could influence the processing from pri-miR-30c to mature miR-30c, but does not influence the transcription of pri-miR-30c.

Objective: To investigate the performance of random forest method as a SNP screening procedure in high dimensional case-control data of lung cancer., Methods: This study included 500 lung cancer patients and 517 controls. A total of 5 ml venous blood sample was collected from each participant. The genotypes were classified by GoldenGate platform, and 399 SNPs were selected. The random forest method was first applied to reduce the dimension, and then the traditional logistic regression method was used to analyze the variables and the genetic susceptibility between lung cancer and multiple SNPs was analyzed by AUC (areas under receiver operation characteristics (ROC) curves)., Results: Fifty important variables, whose average importance scores were highest and whose error rates were lowest, were selected by random forest method. The importance scores of environmental variables (smoking, age and gender) were all listed at top 20, which were respectively 4.05, 3.12 and 1.16. After adjusting 3 environmental variables and false discovery rate (FDR), 6 SNPs were still significantly associated with lung cancer (FDR-P < 0.05). However, if traditional logistic regression analysis were directly applied, no significant SNPs were found. The likelihood testing result of AUC of the 2 ROC (one curve only included environmental variables and the other curve included environmental variables and SNPs) were 0.6491 ± 0.0172 and 0.6811 ± 0.0166 respectively; showed statistical significance of the association between the 6 SNPs and lung cancer (χ² = 43.82, P = 3.6×10⁻¹¹)., Conclusion: Random forest analysis could first remove the turbulent SNPs and then make the analysis by logistic regression method. This could improve the testing efficacy, which is significantly better than single logistic regression analysis.

Objective: The PI3K/PTEN/AKT/mTOR signaling pathway has been implicated in resistance to cisplatin. In the current study, we determined whether common genetic variations in this pathway are associated with platinum-based chemotherapy response and clinical outcome in advanced non-small cell lung cancer (NSCLC) patients., Methods: Seven common single nucleotide polymorphisms (SNPs) in core genes of this pathway were genotyped in 199 patients and analyzed for associations with chemotherapy response, progression-free survival (PFS) and overall survival (OS)., Results: Logistic regression analysis revealed an association between AKT1 rs2494752 and response to treatment. Patients carrying heterozygous AG had an increased risk of disease progression after two cycles of platinum-based chemotherapy compared to those with AA genotype (Adjusted odds ratio (OR)=2.18, 95% confidence interval (CI): 1.00-4.77, which remained significant in the stratified analyses). However, log-rank test and cox regression detected no association between these polymorphisms in the PI3K pathway genes and survival in advanced NSCLC patients., Conclusions: Our findings suggest that genetic variants in the PI3K/PTEN/AKT/mTOR pathway may predict platinum-based chemotherapy response in advanced NSCLC patients in a Chinese population.

Objective: NBS1 plays a key role in the repair of DNA double-strand break (DSB). We conducted this study to investigate the effect of two critical polymorphisms (rs1805794 and rs13312840) in NBS1 on treatment response and prognosis of advanced non-small cell lung cancer (NSCLC) patients with platinum-based chemotherapy., Methods: Using TaqMan methods, we genotyped the two polymorphisms in 147 NSCLC patients. Odds ratios (ORs) and their 95% confidential intervals (CIs) were calculated as a measure of difference in the response rate of platinum-based chemotherapy using logistic regression analysis. The Kaplan-Meier and log-rank tests were used to assess the differences in progression-free survival (PFS) and overall survival (OS). Cox proportional hazards model was applied to assess the hazard ratios (HRs) for PFS and OS., Results: Neither of the two polymorphisms was significantly associated with treatment response of platinum-based chemotherapy. However, patients carrying the rs1805794 CC variant genotype had a significantly improved PFS compared to those with GG genotype (16.0 vs. 8.0 months, P = 0.040). Multivariable cox regression analysis further showed that rs1805974 was a significantly favorable prognostic factor for PFS [CC/CG vs. GG: Adjusted HR = 0.62, 95% CI: 0.39-0.99; CC vs. CG/GG: Adjusted HR = 0.56, 95% CI: 0.32-0.97). Similarly, rs13312840 with a small sample size also showed a significant association with PFS (CC vs. CT/TT: Adjusted HR = 25.62, 95% CI: 1.53-428.39)., Conclusions: Our findings suggest that NBS1 polymorphisms may be genetic biomarkers for NSCLC prognosis especially PFS with platinum-based chemotherapy in the Chinese population.

A general analysis method is proposed that utilizes meta-analysis to incorporate similar studies in addition to our current investigation in order to obtain informative prior effect parameters in a logistic regression model. It is common in epidemiological studies that data from similar previous studies are available. The case of gene susceptibility association with increased lung cancer frequency was used to demonstrate this methodology. Results of Markov chain Monte Carlo (MCMC) iterations provided a more precise estimation of the regression coefficient in a logistic model with informative prior distribution compared to the noninformative prior distribution model. In situations where similar historical data are available, it is proposed to include as much relevant information as previously published results in the analysis of current data.

Objective: To explore the relationship between two exonic polymorphisms of DNA repair gene XPC and the susceptibility to lung cancer., Methods: Genotypes were determined by the primer introduced restriction analysis-PCR(PIRA-PCR) and the PCR-restriction fragment length polymorphism(PCR-RFLP) approaches, respectively, in 320 histologically-confirmed lung cancer cases and 322 age and sex frequency-matched cancer-free controls., Results: Multivariate logistic regression analysis revealed that individuals carrying at least one 499Val variant allele (Ala/Val + Val/Val genotypes) had a significantly increased risk for lung cancer (adjusted OR=1.54; 95%CI: 1.11-2.14), compared with the wild-type genotype (499Ala/Ala). Furthermore, individuals with both putative risk genotypes had a significantly higher risk (adjusted OR=2.55; 95%CI: 1.45-4.52), compared with those with both wild-genotypes. In addition, a potential super multiplicative gene-environment interaction between Ala499Val genotypes and smoking on lung cancer risk was unveiled. The odds ratios of lung cancer for individuals with both putative risk genotypes were 2.63 (95%CI=1.23-5.62) in nonsmokers and 7.36 (95%CI=3.19-17.0) in smokers, respectively., Conclusion: These findings support the hypothesis that these two XPC variants may contribute to the risk of developing lung cancer.

Objective: To study the relationship between two potential functional polymorphisms in exon 2 of the p73 gene and the susceptibility of lung cancer., Methods: Genotypes were determined by polymerase chain reaction-single stand conformation polymorphism (PCR-SSCP) method in 425 histologically-confirmed lung cancer cases and 588 cancer-free controls, frequency-matched by age and sex., Results: The two polymorphisms were in complete linkage disequilibrium and the frequencies of variant p73 AT haplotype (A4T14) were less commonly seen in the cases (0.225) than in the controls (0.287) (P = 0.0018). Compared with the p73 GC/GC homozygotes, both the AT/AT variant homozygotes and GC/AT heterozygotes were associated with a significantly decreased risk [adjusted odds ratio (OR) = 0.45, 95% confidence interval (CI) = 0.26 - 0.80 and OR = 0.70, 95% CI = 0.53-0.92, respectively]., Conclusion: These results suggested that this p73 dinucleotide polymorphism might have had a role to play in the susceptibility of lung cancer.