Genetic variations in XRCC2 and XRCC3 are not associated with endornetrial cancer risk
Genetic variations in XRCC2 and XRCC3 are not associated with endornetrial cancer risk
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DOI：
10.1158/1055-9965.epi-03-0332
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发表时间：
2004-02-01
影响因子：
3.8
通讯作者：
De Vivo, I
中科院分区：
文献类型：
--
作者：
Han, JL;Hankinson, SE;De Vivo, I
材料和方法这项巢式病例对照研究（病例，n = 220；对照，n = 666）包括截至 1998 年 6 月 1 日从护士健康研究的血液子队列中诊断出的流行病例和经病理证实的事件子宫内膜癌病例。对照组与病例在出生年份、抽血时的绝经状态和抽血时的激素替代治疗状态上进行匹配（3:1）。病例和对照的特征已在前面描述过 (4)。使用 ABI Prism 7900HT 序列检测系统（Applied Biosystems，Foster City，CA）通过 5'-核酸酶测定（TaqMan）进行基因分型测定。基因分型由不了解病例对照状态的实验室人员进行，并插入不知情的质量控制样本来验证基因分型程序；盲样样本的一致性为100%。使用条件逻辑回归计算优势比 (OR) 和 95% 置信区间 (CI)。我们使用 ARLEQUIN 2.0 软件包推断单倍型 (5)。结果我们没有观察到四种基因型与子宫内膜癌风险的总体关联（表 1 和表 2）。我们观察到，与 XRCC2 31479 G/G 基因型相比，G/A 和 A/A 基因型的多变量 OR 分别为 0.95 (95% CI, 0.58–1.54) 和 2.05 (95% CI, 0.24–17.82)。 XRCC3 中的三种常见单倍型占本研究群体染色体的 99%。与 XRCC3 4541A 纯合女性相比，4541G 等位基因杂合女性的多变量风险为 1.00（95% CI，0.69–1.43），4541G 等位基因纯合女性的多变量风险为 0.75（95% CI，0.30–1.87）。与非携带者相比，携带一个 XRCC3 17893G 等位基因和两个等位基因的女性的多变量 OR 分别为 0.95 (95% CI，0.66–1.36) 和 0.69 (95% CI，0.39–1.21)，携带至少一个 G 的 OR 为 0.89 (95% CI，0.63–1.25)。等位基因。与具有 18067 C/C 基因型的女性相比，具有 C/T 和 T/T 基因型的女性的多变量 OR 分别为 1.03 (95% CI, 0.72–1.47) 和 1.15 (95% CI, 0.67–1.98)。这些多态性与体重指数、体重增加和吸烟（包年）等风险因素之间没有观察到显着的相互作用。讨论我们既没有观察到 XRCC2 和 XRCC3 多态性与子宫内膜癌风险的关联，也没有观察到病例和对照中 XRCC3 单倍型分布的显着差异。相当多的病例、前瞻性的协变量信息收集以及高随访率增强了本研究的有效性。考虑到对照中的样本量和等位基因频率，我们对 XRCC2 G31479A 的功效为 95%，对三个 XRCC3 多态性的功效为 99%，检测变异等位基因携带者与非携带者的 OR 为 2.0。体外实验研究了两种多态性 XRCC2 G31479A (R188H) 和 XRCC3 C18067T (T241M) 对丝裂霉素 C 诱导的 DNA 链间交联后细胞存活的功能影响 (6, 7)。这两种变体都没有对损伤敏感性产生显着影响。最近评估了 XRCC2 和 XRCC3 基因的遗传变异与乳腺癌风险的关系。这是第一篇关于 HRR 多态性和子宫内膜癌风险的文章。总之，我们没有提供证据表明具有 XRCC2 和 XRCC3 基因多态性的女性患子宫内膜癌的风险发生改变。
Materials and MethodsThis nested case-control study (cases, n= 220; controls, n= 666) included both prevalent and incident pathologically confirmed endometrial cancer cases diagnosed up to June 1, 1998, from the blood subcohort of the Nurses’ Health Study. Controls were matched to cases (3: 1) on year of birth, menopausal status at blood draw, and hormone replacement therapy status at blood draw. The characteristics of cases and controls have been described previously (4). Genotyping assays were performed by the 5′-nuclease assay (TaqMan) using the ABI Prism 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA). Genotyping was performed by laboratory personnel blinded to case-control status, and blinded quality control samples were inserted to validate genotyping procedures; concordance for the blinded samples was 100%. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. We inferred haplotypes using the ARLEQUIN 2.0 software package (5).ResultsWe observed no overall associations of the four genotypes with endometrial cancer risk (Tables 1 and 2). We observed that, compared with the XRCC2 31479 G/G genotype, the multivariate ORs for the G/A and A/A genotypes were 0.95 (95% CI, 0.58–1.54) and 2.05 (95% CI, 0.24–17.82), respectively. Three common haplotypes in XRCC3 accounted for 99% of chromosomes in the present study population. As compared with women who were homozygous for XRCC3 4541A, women who were heterozygous for 4541G allele had a multivariate risk of 1.00 (95% CI, 0.69–1.43), and women who were homozygous for 4541G allele had a multivariate risk of 0.75 (95% CI, 0.30–1.87). As compared with noncarriers, the multivariate ORs for women with one XRCC3 17893G allele and two alleles were 0.95 (95% CI, 0.66–1.36) and 0.69 (95% CI, 0.39–1.21), respectively, with an OR of 0.89 (95% CI, 0.63–1.25) for carriage of at least one G allele. As compared with women with 18067 C/C genotype, women with C/T and T/T genotypes had multivariate OR of 1.03 (95% CI, 0.72–1.47) and 1.15 (95% CI, 0.67–1.98), respectively. No significant interactions were observed between these polymorphisms and risk factors such as body mass index, weight gain, and smoking (pack-years).DiscussionWe observed neither associations of XRCC2 and XRCC3 polymorphisms with endometrial cancer risk, nor significant differences in XRCC3 haplotype distribution in cases and controls. The fairly large number of cases, the prospective collection of covariate information, and the high follow-up rates strengthen the validity of this study. Given the sample size and the allele frequencies among controls, we had 95% power for the XRCC2 G31479A and 99% for the three XRCC3 polymorphisms of detecting the OR of 2.0 for the variant allele carriers versus noncarriers. The functional effects of the two polymorphisms XRCC2 G31479A (R188H) and XRCC3 C18067T (T241M) on cell survival after mitomycin C-induced DNA interstrand cross-linking have been studied in in vitro experiments (6, 7). Neither of the two variants displayed a significant effect on damage sensitivity. Genetic variations in XRCC2 and XRCC3 genes have recently been evaluated in relation to breast cancer risk. This is the first article of polymorphisms in HRR and endometrial cancer risk. In summary, we did not provide evidence that women with the polymorphisms in XRCC2 and XRCC3 genes had an altered risk of endometrial cancer.