Jang Jin Sung, Kim Kyung Mee, Kang Kyung Hee, Choi Jin Eun, Lee Won Kee, Kim Chang Ho, Kang Young Mo, Kam Sin, Kim In-San, Jun Jae Eun, Jung Tae Hoon, Park Jae Yong
Cancer Research Institute, Kyungpook National University School of Medicine, Daegu 700-422, Republic of Korea.
Department of Internal Medicine, Kyungpook National University Hospital, Daegu 700-412, Republic of Korea.
Lung Cancer. 2008 Apr;60(1):31-39. doi: 10.1016/j.lungcan.2007.09.008. Epub 2007 Oct 24.
Survivin is an apoptosis inhibitor and plays an important role in the development and progression of cancer. Polymorphisms in the survivin gene may influence survivin production or activity, thereby modulating susceptibility to lung cancer. To test this hypothesis, we investigated the association between survivin polymorphisms and the risk of lung cancer in a Korean population.
We first screened for polymorphisms in the survivin gene by direct sequencing of genomic DNA samples from 27 healthy Koreans. We selected identified SNPs based on their frequency, linkage disequilibrium status and haplotype tagging status, and then genotyped the selected SNPs in 582 lung cancer patients and 582 healthy controls who were frequency matched for age and gender.
We identified 8 single nucleotide polymorphisms (SNPs): 6 known SNPs [-644T>C, -625G>C, -31C>G, 9194A>G (K129E), 9386T>C and 9809T>C] and 2 novel SNPs (9974C>T and 10347G>A). Among the SNPs studied, only the -31C>G genotype distribution was significantly different between the cases and controls (P=0.04). Individuals with at least one -31G allele were at a significantly decreased risk of lung cancer compared to those individuals with the -31CC genotype [adjusted odds ratio (OR)=0.74, 95% confidence interval (CI)=0.57-0.96, P=0.02]. When the lung cancer cases were categorized by tumor histology, the -31G allele was associated with a significantly decreased risk of adenocarcinoma (adjusted OR=0.59, 95% CI=0.41-0.84, P=0.003). Consistent with the results of the genotyping analysis, the -625G/-31G/9194A/9809T haplotype carrying the -31G allele was associated with a significantly decreased risk of adenocarcinoma (adjusted OR=0.56, 95% CI=0.40-0.77, P=0.0004). The promoter assay revealed the -31G allele to have a significantly lower promoter activity than the -31C allele.
These results suggest that the survivin -31C>G polymorphism influences survivin expression, thus contributing to the genetic susceptibility to lung cancer.
Survivin是一种凋亡抑制因子,在癌症的发生和发展中起重要作用。Survivin基因多态性可能影响Survivin的产生或活性,从而调节肺癌易感性。为验证这一假设,我们在韩国人群中研究了Survivin基因多态性与肺癌风险的关联。
我们首先通过对27名健康韩国人的基因组DNA样本进行直接测序来筛查Survivin基因的多态性。我们根据其频率、连锁不平衡状态和单倍型标签状态选择已鉴定的单核苷酸多态性(SNP),然后对582例肺癌患者和582名年龄和性别频率匹配的健康对照进行所选SNP的基因分型。
我们鉴定出8个单核苷酸多态性(SNP):6个已知SNP [-644T>C、-625G>C、-31C>G、9194A>G(K129E)、9386T>C和9809T>C]和2个新SNP(9974C>T和10347G>A)。在所研究的SNP中,仅-31C>G基因型分布在病例组和对照组之间有显著差异(P=0.04)。与-31CC基因型个体相比,至少有一个-31G等位基因的个体患肺癌的风险显著降低[校正比值比(OR)=0.74,95%置信区间(CI)=0.57-0.96,P=0.02]。当肺癌病例按肿瘤组织学分类时,-31G等位基因与腺癌风险显著降低相关(校正OR=0.59,95%CI=0.41-0.84,P=0.003)。与基因分型分析结果一致,携带-31G等位基因的-625G/-31G/9194A/9809T单倍型与腺癌风险显著降低相关(校正OR=0.56,95%CI=0.40-0.77,P=0.0004)。启动子分析显示-31G等位基因的启动子活性显著低于-31C等位基因。
这些结果表明Survivin -31C>G多态性影响Survivin表达,从而导致肺癌的遗传易感性。