Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk
Evaluation of genetic variation in the double-strand break repair pathway and bladder cancer risk
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DOI：
10.1093/carcin/bgm132
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发表时间：
2007-08-01
期刊：
影响因子：
4.7
通讯作者：
Garcia-Closas, Montserrat
中科院分区：
文献类型：
--
作者：
Figueroa, Jonine D.;Malats, Nuria;Garcia-Closas, Montserrat
双链断裂DNA修复（DSBR）途径与维持基因组稳定性有关，因此可能影响膀胱癌风险。在这里，我们提出了39个单核苷酸多态性（SNPs）在7个候选基因，其产品涉及DNA断裂传感（NBS 1，BRCA 1相互作用基因BRIP 1和ZNF 350），非同源末端连接（NHEJ）DNA修复（XRCC 4）和同源重组（HR）修复（RAD 51，XRCC 2和XRCC 3）的数据评估。RAD 51和XRCC 2的SNP覆盖了大多数常见变异。在1997-2001年期间在西班牙进行的1150例新诊断的膀胱移行细胞癌和1149例对照中，评估了膀胱癌风险的相关性。我们发现，评估的遗传变异显着有助于膀胱癌的风险（全局似然比检验P = 0.01）。ZNF 350 R501 S（rs 2278415）变异等位基因的受试者与常见的纯合子变异相比，风险显著降低，比值比（OR）[95%置信区间（95%CI）]：每个变异等位基因0.76（0.62-0.93）。与普通纯合子相比，XRCC 4内含子7（rs 1805377）中假定功能SNP的携带者具有显著增加的膀胱癌风险：每个变异等位基因1.33（1.08-1.64）。最后，三个启动子SNP（rs 10234749，rs6464268，rs3218373）和一个非同义SNP（rs3218536，R188 H）的XRCC 2纯合子变体与膀胱癌风险降低相关（与普通纯合子相比，OR范围为0.36至0.50）。XRCC 3 T241 M（rs 861539）的荟萃分析显示，纯合子变异体的风险显著小幅增加：OR（95% CI）= 1.17（1.00-1.36）。这项研究的结果为DSBR通路中的基因变异与膀胱癌风险之间的关联提供了证据，这些证据值得在其他研究人群中复制。
The double-strand break DNA repair (DSBR) pathway is implicated in maintaining genomic stability and therefore could affect bladder cancer risk. Here we present data evaluating 39 single-nucleotide polymorphisms (SNPs) in seven candidate genes whose products are involved in DNA break sensing (NBS1, BRCA1 interacting genes BRIP1 and ZNF350), non-homologous end-joining (NHEJ) DNA repair (XRCC4) and homologous recombination (HR) repair (RAD51, XRCC2 and XRCC3). SNPs for RAD51 and XRCC2 covered most of the common variation. Associations with bladder cancer risk were evaluated in 1150 newly diagnosed cases of urinary bladder transitional cell carcinomas and 1149 controls conducted in Spain during 1997-2001. We found that the genetic variants evaluated significantly contributed to bladder cancer risk (global likelihood ratio test P = 0.01). Subjects with the ZNF350 R501S (rs2278415) variant allele showed significantly reduced risk compared with common homozygote variants, odds ratio (OR) [95% confidence interval (95% CI)]: 0.76 (0.62-0.93) per variant allele. Carriers of a putative functional SNP in intron 7 of XRCC4 (rs1805377) had significantly increased bladder cancer risk compared with common homozygotes: 1.33 (1.08-1.64) per variant allele. Lastly, XRCC2 homozygote variants for three promoter SNPs (rs10234749, rs6464268, rs3218373) and one non-synonymous SNP (rs3218536, R188H) were associated with reduced bladder cancer risk (ORs ranging from 0.36 to 0.50 compared with common homozygotes). Meta-analysis for XRCC3 T241M (rs861539) had a significant small increase in risk among homozygote variants: OR (95% CI) = 1.17 (1.00-1.36). Results from this study provide evidence for associations between variants in genes in the DSBR pathway and bladder cancers risk that warrant replication in other study populations.