ABSTRACT
ABSTRACT BACKGROUND: There is evidence that genetic predisposition and epigenetic alteration (e.g. DNA methylation) play major roles in lung cancer. In our genetic epidemiological studies, rs1970764 in oncogene PPP1R13L was most consistently associated with lung cancer risk. Here, we explored the role of PPP1R13L methylation in lung cancer development. DESIGN AND SETTING: Analytical cross-sectional study (45 lung cancer cases and 45 controls), conducted in China. METHODS: We investigated the DNA methylation status of 2,160 cytosine-phosphate-guanine (CpG) sites in the PPP1R13L promoter region using the EpiTYPER assay of the Sequenom MassARRAY platform. RESULTS: In the whole study group, the methylation levels of CpG-6, CpG-9, CpG-20 and CpG-21 were significantly lower and those of CpG-16 were significantly higher in cases than in controls. Among smokers, the methylation levels at five CpG sites (CpG-6, CpG-11, CpG-15, CpG-20 and CpG-21) were statistically significantly lower among cases. Among men, the methylation levels at four CpG sites (CpG-11, CpG-15, CpG-20 and CpG-21) were significantly lower among cases. Regarding smokers, the methylation levels at CpG-7.8 and CpG-21 among cases and at CpG-22 among controls were significantly lower, compared with nonsmokers. The frequency of positivity for methylation was not significantly different between lung cancer cases and controls (68.22% for cases and 71.87% for controls; P = 0.119). CONCLUSION: Our study on a Chinese population suggests that lung cancer patients have aberrant methylation status (hypomethylation tended to be more frequent) in peripheral blood leukocytes at several CpG sites in the PPP1R13L promoter region and that exposure to smoking may influence methylation status.
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Repressor Proteins/genetics , DNA Methylation/genetics , Genetic Predisposition to Disease/genetics , Intracellular Signaling Peptides and Proteins/genetics , Lung Neoplasms/genetics , Case-Control Studies , Cross-Sectional Studies , Promoter Regions, GeneticABSTRACT
Genetic variants in glioma tumor suppressor candidate region gene 1 (GLTSCR1)and ATM serine/threonine kinase (ATM) have been associated with various cancer risks.Epidemiological studies also revealed the association of variants of GLTSCR1 and ATM genes with different brain tumors.However,little is known about the relationship between both gene polymorphisms and lung cancer risk.We conducted a Chinese hospital-based casecontrol study involving 384 lung cancer cases and 387 cancer-free controls.No significant differences in the single polymorphism (GLTSCR1 rs1035938 and ATM rs11212592)association were found in five genetic models (co-dominant,dominant,recessive,overdominant and log-additive models) (adjusted by smoking duration).Join effect of three SNPs (PPP1R13L rs1970764,CD3EAP rs967591,GLTSCR1 rs1035938) on chromosome 19q 13.3 showed that the designated haplotype2 (rs 1970764<rs967591A-rs 1035938c) [OR (95％ CI)=1.60 (1.11-2.32),P=0.012] and haplotype8 (rs 1970764G-rs967591G-rs 1035938T)[OR (95％ CI)=2.45 (1.17-5.12),P=0.018] were associated with increased risk of lung cancer (adjusted by smoking duration).The analysis ofmultifactor dimensionality reduction revealed that two 3-way models were the best fit models in analyses of 2 loci (P＜0.001)or 4 loci (P=0.015-0.016).The entropy-based analysis indicated the strongest synergistic effect between PPP1R13L rs1970764 and ATM rs11212592 in analysis of four genes.In conclusion,our study suggests that haplotypes consisting of PPP1R13L rs1970764-CD3EAP rs967591-GLTSCR1 rs1035938 on Chr19q13.3,interaction of smoking and GLTSCR1 rs1035938-ATM rs11212592,and synergistic action of PPP1R13L rs1970764 and ATMrs11212592 may associate with lung cancer risk in the Chinese population.
ABSTRACT
Genetic variants in glioma tumor suppressor candidate region gene 1 (GLTSCR1)and ATM serine/threonine kinase (ATM) have been associated with various cancer risks.Epidemiological studies also revealed the association of variants of GLTSCR1 and ATM genes with different brain tumors.However,little is known about the relationship between both gene polymorphisms and lung cancer risk.We conducted a Chinese hospital-based casecontrol study involving 384 lung cancer cases and 387 cancer-free controls.No significant differences in the single polymorphism (GLTSCR1 rs1035938 and ATM rs11212592)association were found in five genetic models (co-dominant,dominant,recessive,overdominant and log-additive models) (adjusted by smoking duration).Join effect of three SNPs (PPP1R13L rs1970764,CD3EAP rs967591,GLTSCR1 rs1035938) on chromosome 19q 13.3 showed that the designated haplotype2 (rs 1970764<rs967591A-rs 1035938c) [OR (95％ CI)=1.60 (1.11-2.32),P=0.012] and haplotype8 (rs 1970764G-rs967591G-rs 1035938T)[OR (95％ CI)=2.45 (1.17-5.12),P=0.018] were associated with increased risk of lung cancer (adjusted by smoking duration).The analysis ofmultifactor dimensionality reduction revealed that two 3-way models were the best fit models in analyses of 2 loci (P＜0.001)or 4 loci (P=0.015-0.016).The entropy-based analysis indicated the strongest synergistic effect between PPP1R13L rs1970764 and ATM rs11212592 in analysis of four genes.In conclusion,our study suggests that haplotypes consisting of PPP1R13L rs1970764-CD3EAP rs967591-GLTSCR1 rs1035938 on Chr19q13.3,interaction of smoking and GLTSCR1 rs1035938-ATM rs11212592,and synergistic action of PPP1R13L rs1970764 and ATMrs11212592 may associate with lung cancer risk in the Chinese population.