Association Of CYP1A1 Polymorphisms With Lung Cancer Risk And MIF Regulating Cell Cycle Pathway Genes Polymorphisms With The Clinical Outcomes Of Platinum-based Chemotherapy In Advanced Non-small-cell Lung Cancer

Part 1:Meta-analysis of CYP1A1 polymorphisms and iung cancer risk among smokersAbstract: This meta-analysis investigated the relationship between CYP1A1 gene polymorphisms and susceptibility to lung cancer among smokers. All of the publications were eligible from some main databases and the information about relationship between CYP1A1 Ile462Val and Mspl polymorphisms and lung cancer risk among smokers was summarized. Meta-analysis was performed using RevMan 4.2.29 case-control studies were available. For Ile462Val, meta-analysis revealed that the risk of lung cancer among smokers with Val/Val and Ile/Val genotypes was 1.29 times of those with Ile/Ile genotype (P<0.05) by the random effects model. There was no significant correlation between Mspl and lung cancer among smokers or non-smokers. These results suggest that CYP1A1 Ile462Val polymorphism is related to the susceptibility of lung cancer among smokers.Part 2:Novel association of MIF regulating cell cycle pathway genes polymorphisms with the clinical outcomes of platinum-based chemotherapy in advanced non-small-cell lung cancerAbstract: Platinum-based regimens could generate DNA damage. MIF performed a significant function in the G2M DNA damage checkpoint response and regulation of cell cycle through controlling the activity of SCF complex. We assumed a pathway-based approach in the interest of investigating the association of genetic polymorphisms of the corresponding genes with the outcomes of platinum-based chemotherapy in advanced non-small-cell lung cancer (NSCLC).We used illumina iSelect 24×1 HD for genotyping 32 polymorphisms of 8 genes and evaluated the associations with the outcomes in 1004 advanced NSCLC patients treated with platinum-based chemotherapy. A polymorphism of CD74(rs 1560661) was most significantly associated with hematological toxicity(adjusted OR,0.38,95%CI, 0.23-0.65,P=0,00035;P for Bonferroni correction,0.011),in accordance with the haplotype ACAG (adjusted OR,0.70,95%CI 0.57-0.87,P=0.0012,P for Bonferroni correction,0.0384), whereas two haplotypes of Cull(ACAAGAGGAGG and GCCAGAGAAAG)seemed to increase the weight of gastrointestinal toxicity (adjusted OR,2.71;95%CI,1.62-4.52,P=0.000139;adjusted OR,2.45;95% CI, 1.48-4.06,P=0.0005).And all were in agreement with the corresponding diplotype analysis.MDR analysis consistently suggested the haplotype CG of CD74 and rs243482 of Cull as the strongest individual factor for hematologic and gastrointestinal toxicity risk respectively.The interaction among rs6997490 of Jabl, rs11158615 of Nedd8 and rs243523 of Cull gave the best model for hematologic toxicity predication with testing balance accuracy 0.569(P<0.0001,CVC,100/100), whereas for the latter a five-factor model including block of MIF(rs2012124 and rs4822443),Jab1,block of Nedd8,blodk of Cand1 and rs243482 of Cull yieleing the highest testing accuracy of 0.801(P<0.0001,CVC,100/100).Our study, for the first time, suggested that polymorphisms fo MIF regulating cell cycle pathway genes might be a prognostic marker for advanced NSCLC patients receiving platinum-based chemotherapy.