Genetic variation in the nucleotide excision repair pathway and colorectal cancer risk
Genetic variation in the nucleotide excision repair pathway and colorectal cancer risk
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DOI：
10.1158/1055-9965.epi-06-0449
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发表时间：
2006-11-01
影响因子：
3.8
通讯作者：
Helzlsouer, Kathy J.
中科院分区：
文献类型：
--
作者：
Berndt, Sonja I.;Platz, Elizabeth A.;Helzlsouer, Kathy J.
核苷酸切除修复(NER)酶对于去除由环境致癌物引起的大量DNA加合物至关重要，如杂环胺和多环芳烃，这些物质存在于两个可能导致结直肠癌的危险因素中，烟草烟雾和高温烹调的肉类。为了研究NER基因中常见的遗传变异与结直肠癌风险之间的关系，我们在CLUE II队列中进行了一项病例队列研究。在250例结直肠癌病例和2224名参与者中，对11个NER基因的22个单核苷酸多态进行了基因分型。发病率比(RR)和95%可信区间(95%CI)用改进的COX回归模型和稳健方差估计来估计。ERCC61213G变异被认为降低了NER的能力，与野生型纯合子相比，RG和GG基因型患结直肠癌的风险增加，RG和GG基因型的95%可信区间分别为1.00~1.86和2.64；95%可信区间为1.53~4.58，P趋势=0.0006。至少有一个XPC 492H等位基因也与结直肠癌风险增加相关(RR，1.75；95%CI，1.20-2.57)。当考察ERCC6R1213G和XPC R492H的联合作用时，随着变异等位基因数目的增加，患结直肠癌的风险显著增加(P趋势=0.00003)。我们的研究表明，NER基因ERCC6和XPC的遗传多态可能与结直肠癌风险增加有关。
Nucleotide excision repair (NER) enzymes are critical for the removal of bulky DNA adducts caused by environmental carcinogens, such as heterocyclic amines and polycyclic aromatic hydrocarbons, which are found in two putative risk factors for colorectal cancer, tobacco smoke and meat cooked at high temperature. To examine the association between common genetic variants in NER genes and the risk of colorectal cancer, we conducted a case-cohort study within the CLUE II cohort. Twenty-two single nucleotide polymorphisms in 11 NER genes were genotyped in 250 colorectal cancer cases and a subcohort of 2,224 participants. Incidence rate ratios (RR) and 95% confidence intervals (95% CI) were estimated using a modified Cox regression model and robust variance estimate. The ERCC6 1213G variant, which is thought to reduce NER capacity, was associated with an increased risk of colorectal cancer compared with the homozygous wild type MR, 1.36; 95% CI, 1.00-1.86 and RR, 2.64; 95% CI, 1.53-4.58 for the RG and GG genotypes respectively with P-trend = 0.0006). Having at least one XPC 492H allele was also associated with an increased risk of colorectal cancer (RR, 1.75; 95% CI, 1.20-2.57). When the combined effects of ERCC6 R1213G and XPC R492H were examined, the risk of colorectal cancer significantly increased with increasing number of variant alleles (Ptrend = 0.00003). Our study suggests that genetic polymorphisms in the NER genes, ERCC6 and XPC, may be associated with an increased risk of colorectal cancer.