The Ahr And Ppar-¦Ã Gene Polymorphism And Cancer Genetic Susceptibility

PartⅠLung cancer is the leading cause of cancer deaths in the world with a poor prognosis and an overall 5-year survival rate of＜15%.The epidemic of lung cancer is directly attributable to cigarette smoking that accounts for 87 percent of lung cancer cases.However,only a small fraction of smokers(usually＜20%)develop lung cancer in their lifetime.It is well established that susceptibility to lung cancer may in part be attributable to inter-individual variation in metabolic activation or detoxification of tobacco carcinogens,suggesting the importance of genetic determinants in lung cancer etiology,including the gene-environment interaction between genetic polymorphisms and environmental factors,such as smoking.Most of the carcinogenic effects of polycyclic aromatic hydrocarbons(PAHs) present in tobacco smoke are mediated by the aryl hydrocarbon receptor(AHR),a ligand-dependent transcription factor that regulates tobacco-induced expression of carcinogen metabolic enzymes.To test the hypothesis that genetic variations in AHR may confer individual susceptibility to lung cancer,we genotyped for eight selected single nucleotide polymorphisms(SNPs)in AHR in a case-control study of 500 lung cancer patients and 517 cancer-free controls in a Chinese population.We observed statistically significant differences between case patients and control subjects in genotype distributions for two SNPs(P=0.0038 for rs2158041 and P=0.008 for rs7811989)and the significance remained after applying 100,000-time permutation tests(P=0.0193 for rs2158041 and P=0.0407 for rs7811989).Further logistic regression analyses revealed that the significantly increased lung cancer risk was associated with heterozygous genotypes of rs2158041(adjusted odds ratio=1.53 and 95%confidence interval=1.17-1.99 for GA,compared with the GG genotype)and rs7811989(adjusted odds ratio=1.48 and 95%confidence interval=1.13-1.93 for GA, compared with the GG genotype).Furthermore,haplotype analysis revealed significant differences in haplotype distributions of AHR between cases and controls(Global P= 1.38e-5).We also observed statistically significant interaction between the polymorphism rs2066853(p.Arg554Lys)and cumulative cigarette smoking as a discrete or continuous variable(P=0.033 and 0.019,respectively),and the Lys/Lys genotype conferred an increased risk of lung cancer in the heavy smokers(adjusted odds ratio=3.36 and 95%confidence interval=1.07-10.55).These findings suggest that AHR polymorphisms and potential gene-smoking interaction may be involved in the etiology of lung cancer. PartⅡAccumulating evidence indicates that activation of the peroxisome proliferator-activated receptor-γ(PPAR-γ)dampens the inflammation cascade caused by cigarette smoking and inhibits tumor growth of the lung,suggesting that it has tumor suppressor functions in the pathogenesis and progression of human lung cancer.We hypothesized that genetic variation in the PPAR-γgene may have an impact on individual risk of lung cancer.To test this hypothesis,we conducted a case-control study of 500 incident lung cancer cases and 517 age and sex frequency-matched cancer-free controls in a Chinese population,and genotyped 11 single nucleotide polymorphisms (SNPs)of PPAR-γusing an Illumina high-throughput genotyping platform.We also investigated potential interactions between polymorphisms of the PPAR-γgene and cigarette smoking in lung cancer risk.The issue of multiple tests was controlled by using 10,000-time permutation tests.We found,for the first time,that decreased lung cancer risk was statistically significantly associated with seven SNPs(P=0.0004 for rs13073869 and 0.0130 for rsl899951 in a dominant model;P=0.0310 for rs4135247 in a log-additive model;and P=0.0468 for rs2972162,0.0175 for rs709151,0.0172 for rs11715541 and 0.0386 for rs1175543 in an overdominant model).The difference for two SNPs(rs13073869 and rs1899951)remained significant after applying 10,000-time permutation tests. Consistent with these results of single-locus analysis,both the haplotype and diplotype analyses revealed a protective effect of the haplotype 'AGA' and 'AAA' of rs13073869, rs1899951 and rs4135247.The risk of lung cancer was significantly decreased among individuals carrying the haplotype 'AGA'(adjusted OR=0.80 and 95%CI=0.65-0.98), and 'AAA'(adjusted OR=0.57 and 95%CI=0.37-0.87),compared with those carrying the most common haplotype 'GGG' in block 1.Subjects carrying 1～2 copies of the haplotye 'AGA' had a 28%reduced lung cancer risk(adjusted OR=0.72 and 95% CI=0.56-0.93),and those carrying 1～2 copies of 'AAA' had a 42%reduced lung cancer risk(adjusted OR=0.58 and 95%CI=0.37-0.90)compared with their respective non-carriers Furthermore,we observed a statistically significant interaction between the rs1899951 and cigarette smoking.Our results indicate that PPAR-γpolymorphisms and their interaction with smoking may contribute to the etiology of lung cancer.According to the phaseⅡHapMap data on 45 Han Chinese,the rs13073869 polymorphism was in perfect LD(D'=1.00,r~2=1.00)with a OG substitution (rs10865710)in the PPAR-γ~3 regulatory region at position-681 in PPAR-γ~3-specific exon A2(the A allele being associated with the-681 G allele).In vitro,the-681 G allele completely abolished the binding of STAT5B to the cognate promoter element as well as the transactivation of PPAR-γ3 by the growth hormone/STAT5B pathway.Furthermore, rs1899951 is in perfect LD with the non-synonymous polymorphism p.Pro12Ala (rs1801282)in PPAR-γ2-specific exon B(the A allele being associated with the Ala12 allele).This amino acid is located in a PPAR-γ2 domain that enhances ligand independent activation,and the Pro-to-Ala exchange may cause a conformational change in the protein,thus affecting its activity.The exact location and biological functions of the real causal SNPs of the gene is of great interest and warrants further investigation. PartⅢGliomas are the most common primary tumors in the central nervous system(CNS), which account for more than 70%of all brain tumors,with glioblastoma multiformes (GBMs)as the most lethal and aggressive intracranial neoplasm striking adults. Increasing evidence demonstrates that PPAR-γactivation by agonists induce apoptosis and inhibit glioma cell migration and brain invasion in vivo and in vitro.Two functional polymorphisms have been identified in the PPAR-γgene.One is a praline to alanine substitution,located at codon 12(p.Pro12Ala,rs1801282)of the PPAR-γ2-specific exon B,which may cause a conformational change in the protein thus affecting its activity.Another is a C to G variant(c.-681C＞G,rs10865710)in the promoter region for the PPARγ-3 transcript at position-681 from the beginning of exon A2,which completely abolished the binding of STAT5B to the cognate promoter element as well as the transactivation of the PPARγ-3 promoter.The polymorphisms of rs10865710 and rs1899951 which were found to be significantly associated with lung cancer in our study were in perfect LD(D'=1.00,r~2=1.00)with c.-681C＞G and p.Pro12Ala,respectively.We hypothesized that these two functional polymorphisms might be the causal loci and may confer individual susceptibility to glioma.To test this hypothesis,we investigated the association between these two SNPs and glioma risk in a case-control study of 241 glioblastoma cases,284 astrocytoma cases(except glioblastoma),241 other glioma cases,and 824 healthy controls.We found, for the first time,the variant G allele c.-681C＞G was significantly associated with reduced risk of glioblastoma(adjusted OR=0.76;95%CI=0.61-0.96;P=0.020),with the estimated effect following a trend of decreasing magnitude by number of variant alleles (P for trend=0.024).The polymorphism rs1801282 showed a similar trend as rs10865710 toward association in glioblastoma,although it did not reach statistical significance(adjusted OR=0.68;95%CI=0.41-1.15;P=0.151).When the combined effect of these two polymorphisms were examined,the ORs(95%CIs)for glioblastoma were 0.85(0.61-1.18)for subjects possessing only one low-risk allele and 0.50 (0.32-0.79)for those possessing two or three low-risk alleles,compared to subjects without any low-risk allele,suggesting a significant locus dose-response effect on glioblastoma(P for trend=0.004).However,no significant association with risk of astrocytoma and other glioma was observed for p.Pro12Ala or c.-681C＞G in our study. These findings suggest that the functional SNP c.-681C＞G appears to play a significant role in glioblastoma,the most lethal and aggressive primary brain tumor striking adults.