Jin Guangfu, Wang Haifeng, Hu Zhibin, Liu Hongliang, Sun Weiwei, Ma Hongxia, Chen Dan, Miao Ruifen, Tian Tian, Jin Li, Wei Qingyi, Huang Wei, Lu Daru, Shen Hongbing
Department of Epidemiology and Biostatistics, Cancer Research Center of Nanjing Medical University, Nanjing 210029, China.
Lung Cancer. 2008 Jun;60(3):340-6. doi: 10.1016/j.lungcan.2007.11.003. Epub 2008 Feb 20.
Exonuclease 1 (EXO1) is an important nucleases involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. Potentially functional polymorphisms in EXO1 may alter cancer risks by influencing the repair activity of EXO1. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in EXO1 were associated with risk of lung cancer. To test this hypothesis, we genotyped five common SNPs (rs1776177A/G, rs1047840G/A (Glu589Lys), rs1776148G/A (Gly670Glu), rs9350C/T (Leu757Pro) and rs851797T/C) that tag eight SNPs located at exon regions of EXO1 by using the Illumina high-throughput genotyping platform in 500 incident lung cancer cases and 517 cancer-free controls in a Chinese population. Significant differences of allele and genotype distributions were observed in Glu589Lys (rs1047840) of EXO1 between the cases and controls (P=0.028 and 0.025 for allele and genotype distributions, respectively). Logistic regression analyses revealed that individuals carrying the variant 589Lys allele (589Glu/Lys or 589Lys/Lys) had a significantly increased risk of lung cancer [adjusted odds ratio (OR)=1.41, 95% confidential interval (CI)=1.09-1.84] compared with those who carried the wild-type homozygote (589Glu/Glu). Furthermore, we found that haplotype AAGTT was more frequent in cases than in controls (P<0.001 for both two-sided chi(2)-test and 1000 times permutation tests). These results suggest that the EXO1 Glu589Lys polymorphism and its surrounding regions might be genetic susceptibility markers for lung cancer in this study population.
核酸外切酶1（EXO1）是一种重要的核酸酶，参与错配修复系统，有助于维持基因组稳定性、调节DNA重组并介导细胞周期停滞。EXO1中潜在的功能性多态性可能通过影响EXO1的修复活性来改变癌症风险。因此，我们假设EXO1中的单核苷酸多态性（SNP）与肺癌风险相关。为了验证这一假设，我们在中国人群的500例肺癌病例和517例无癌对照中，使用Illumina高通量基因分型平台，对标记位于EXO1外显子区域的8个SNP的5个常见SNP（rs1776177A/G、rs1047840G/A（Glu589Lys）、rs1776148G/A（Gly670Glu）、rs9350C/T（Leu757Pro）和rs851797T/C）进行了基因分型。病例组和对照组之间在EXO1的Glu589Lys（rs1047840）的等位基因和基因型分布上观察到显著差异（等位基因和基因型分布的P值分别为0.028和0.025）。逻辑回归分析显示，与携带野生型纯合子（589Glu/Glu）的个体相比，携带变异型589Lys等位基因（589Glu/Lys或589Lys/Lys）的个体患肺癌的风险显著增加[调整后的优势比（OR）=1.41，95%置信区间（CI）=1.09-1.84]。此外，我们发现单倍型AAGTT在病例组中比对照组更常见（双侧卡方检验和1000次置换检验的P值均<0.001）。这些结果表明，在本研究人群中，EXO1 Glu589Lys多态性及其周围区域可能是肺癌的遗传易感性标记。
