| Lung cancer is the world's highest incidence and mortality of cancer, with the overall 5-year survival rate less than 15%, and threaten human health and life seriously. Smoking is the most important environmental factors of lung cancer,80-90% of lung cancer associated with smoking, but only 10-15% of smokers will get lung cancer, suggesting that genetic polymorphisms play an important role in the development of lung cancer.Human chromosome 5p 15.33 (TERT-CLPTM1L) region contains hTERT and CLPTM1L, these two genes are closely related to important biological processes, such as cell proliferation, aging and tumor differentiation, invasion, metastasis, and apoptosis. Accumulating GWAS reports support a role of 5p15.33 (TERT-CLPTM1L) region gene polymorphisms in lung cancer susceptibility, however, most of these GWAS are mainly focus on the Caucasian population. To investigate association between 5p15.33 (TERT-CLPTM1L) region gene polymorphisms and lung cancer risk in Chinese population, we first genotyped 14 tag SNPs variants of 5p15.33 (TERT-CLPTM1L) region among 784 patients with incident lung cancer and 782 age-and sex-matched cancer-free control participants to screen for any risk-associated SNPs.The results showed that rs2736100 (C> A) C allele increased the risk of lung cancer, in the dominant model, (CA+CC)/AA (adjusted OR=1.55,95%CI= 1.23-1.96; P=0.0002). rs2736098 (C> T) TT homozygous can significantly increase the risk of lung cancer (adjusted OR=1.53,95% CI=1.09-2.51; P=0.013). rs4246742 (T> A) AA homozygous also significantly increased lung cancer risk (adjusted OR=1.48,95%CI=1.06-2.07; P=0.020). Stratified analysis indicated that these three SNPs were associated with the increased risk of adenocarcinoma, we analyzed the combined effect of these three SNPs, as a result, we found individuals with all three rare alleles have higher risk of lung cancer, increased by 60%(adjusted OR=1.60,95% CI-1.28-1.99; P=3.0×10-5) when compared with those with all three common alleles, they also have 88% higher risk of suffering from adenocarcinoma (adjusted OR=1.88,95% CI-1.44-2.45; P=2.98×10-6). After adjusted by rs2736098 and rs4246742, the allele distribution of rs2736100 was still significantly different between patients and control subjects (adjusted OR=1.24,95% CI=1.05-1.48; P=0.014). Then we validate our result in another case-control study including 975 lung cancer patients and 1022 control participants. The results were confirmed, rs2736100 C allele increased the risk of lung cancer. In dominant model, (CA+CC) genotype increased risk of lung cancer by 34%(adjusted OR=1.34,95% CI=1.09-1.65; P=0.005) compared with the AA genotype. The combined analysis of two stage samples indicated that (CA+CC) genotypes increased the risk of lung cancer 43%(adjusted OR=1.43,95%CI=1.23-1.67; P=5.0×10-6) compared with AA genotype, individuals with CA genotype exhibited 44% increased risk of adenocarcinoma (adjusted OR=1.44,95%CI=1.18-1.76; P=3.51×10-4), while individuals with CC genotype exhibited 95% increased risk of adenocarcinoma (adjusted OR=1.95,95%CI=1.53-2.48; P=6.52×10-8)..This study reveals that human chromosome 5p15.33 (TERT-CLPTM1L) region gene polymorphisms are related to cancer susceptibility of Chinese Han population. Human chromosome 8p11 (CHRNB3-CHRNA6) region contains two genes of CHRNB3 and CHRNA6 encode neuronal nicotinic acetylcholine receptor subunit a6β3 subunit, repectly. There are some international GWAS report that the polymorphism of this region are associated with individual smoking behavior and lung cancer susceptibility.To investigate the association between chromosome 8p11 (CHRNB3-CHRNA6) polymorphisms and lung cancer susceptibility in Chinese Han population, we genotyped 6 tag SNPs variants of this region among 784 patients with lung cancer and 782 age- and sex-matched cancer-free control participants to screen for any risk-associated SNPs. The results revealed that rs16891561 TT genotype has a protective effect against lung cancer in people over 60 years old (adjusted OR=0.42, 95%CI=0.20-0.88; P=0.022), female groups (adjusted OR=0.34,95%CI=0.13-0.87; P=0.025), and non-smoking people (adjusted OR=0.32,95%CI=0.13-079; P=0.013). Additionally, rs4236926 TT genotype has a protective effect against lung cancer in people over 60 years old (adjusted OR=0.48,95%CI=0.23-0.99; P=0.048) and non-smoking people (adjusted OR=0.32,95%CI=0.13-0.80; P=0.014). According to pathological type of lung cancer, these two SNPs are associated with adenocarcinomas susceptibility. As to cumulative effect of rs4236926 and rs16891561, in non-smokers strata, lung cancer risk was found to significantly reduced in those who had 3-4 mutant alleles (adjusted OR=0.29,95% CI=0.11-0.71; P=0.007) Furthermore, people containing 3-4 mutant alleles had lower level of smoking doses (mean pack-year=13.2) compared with others.In conclusion,8p11 (CHRNB3-CHRNA6) polymorphisms are related to smoking behavior and lung cancer susceptibility in Chinese Han population. |
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