Yin Jiaoyang, Vogel Ulla, Ma Yegang, Qi Rong, Wang Huiwen
Key Laboratory of Environment and Population Health of University in Liaoning Province, Shenyang Medical College, Shenyang, Liaoning Province, People's Republic of China.
Carcinogenesis. 2009 Jul;30(7):1181-5. doi: 10.1093/carcin/bgp107. Epub 2009 Apr 30.
DNA repair genes have been proposed as candidate cancer susceptibility genes. The excision repair cross-complementing rodent repair deficiency, complementation group 2 (ERCC2)/xeroderma pigmentosum complementary group D (XPD) protein is considered to be a key enzyme in nucleotide excision repair (NER) pathway. To elucidate whether common ERCC2 variants are associated with lung cancer susceptibility, we conducted a case-control study consisting of 339 cases with primary lung cancer and 358 controls matched on age, gender and ethnicity in a Chinese population. Six haplotype tagging single-nucleotide polymorphisms (htSNPs) (rs238403, rs50871, rs3916840, rs238415, rs3916874 and rs1799787) from HapMap database were analyzed, which provide an almost complete coverage of the genetic variations in the ERCC2 gene. Although none of the six htSNPs was individually associated with lung cancer risk, we found that two ERCC2 haplotypes were associated with risk of lung cancer. Haplotype 4 defined by rs238403T-rs50871T-rs3916840C-rs238415C-rs3916874G-rs1799787C and haplotype 7 defined by rs238403C-rs50871G-rs3916840C-rs238415C-rs3916874G-rs1799787C were strongly associated with an increased risk of lung cancer [odds ratio, OR (95% confidence interval, CI) = 2.62 (1.53-4.50), P = 0.0003 for hap4; OR (95% CI) = 3.01 (1.36-6.63), P = 0.004 for hap7]. Furthermore, diplotype analyses also strengthened the significant associations of risk haplotype 4 [OR (95% CI) = 3.56 (2.12-5.87), P < 0.001] or risk haplotype 7 [OR (95% CI) = 3.38 (1.75-6.55), P < 0.001] and lung cancer. Analysis of linkage disequilibrium (LD) also confirmed that considerable LD exists between the pairs of the six htSNPs within ERCC2. These results suggested that the risk subhaplotypes cosegregate with one or more biologically functional polymorphisms. Our results provide evidence to support a role for ERCC2 in lung cancer development in a Chinese population.
DNA修复基因已被提议作为候选癌症易感基因。切除修复交叉互补啮齿动物修复缺陷互补组2（ERCC2）/着色性干皮病互补组D（XPD）蛋白被认为是核苷酸切除修复（NER）途径中的关键酶。为了阐明常见的ERCC2变异是否与肺癌易感性相关，我们在中国人群中进行了一项病例对照研究，该研究包括339例原发性肺癌病例和358例在年龄、性别和种族上匹配的对照。分析了来自HapMap数据库的六个单倍型标签单核苷酸多态性（htSNP）（rs238403、rs50871、rs3916840、rs238415、rs3916874和rs1799787），这些htSNP几乎完全覆盖了ERCC2基因的遗传变异。虽然这六个htSNP中没有一个单独与肺癌风险相关，但我们发现两个ERCC2单倍型与肺癌风险相关。由rs238403T-rs50871T-rs3916840C-rs238415C-rs3916874G-rs1799787C定义的单倍型4和由rs238403C-rs50871G-rs3916840C-rs238415C-rs3916874G-rs1799787C定义的单倍型7与肺癌风险增加密切相关[优势比，OR（95%置信区间，CI）=2.62（1.53 - 4.50），单倍型4的P = 0.0003；OR（95%CI）=3.01（1.36 - 6.63），单倍型7的P = 0.004]。此外，双倍型分析也强化了风险单倍型4[OR（95%CI）=3.56（2.12 - 5.87），P < 0.001]或风险单倍型7[OR（95%CI）=3.38（1.75 - 6.55），P < 0.001]与肺癌之间的显著关联。连锁不平衡（LD）分析也证实，ERCC2内的六个htSNP对之间存在相当程度的LD。这些结果表明，风险亚单倍型与一个或多个生物学功能多态性共分离。我们的结果提供了证据，支持ERCC2在中国人群肺癌发生中的作用。
