O'Mara Tracy A, Ferguson Kaltin, Fahey Paul, Marquart Louise, Yang Hannah P, Lissowska Jolanta, Chanock Stephen, Garcia-Closas Montserrat, Thompson Deborah J, Healey Catherine S, Dunning Alison M, Easton Douglas F, Webb Penelope M, Spurdle Amanda B
Hormone Dependent Cancer Program, Institute of Health and Biomedical Innovation, Queensland University of Technology, Australia.
Twin Res Hum Genet. 2011 Aug;14(4):328-32. doi: 10.1375/twin.14.4.328.
Several single nucleotide polymorphisms (SNPs) in candidate genes of DNA repair and hormone pathways have been reported to be associated with endometrial cancer risk. We sought to confirm these associations in two endometrial cancer case-control sample sets and used additional data from an existing genome-wide association study to prioritize an additional SNP for further study. Five SNPs from the CHEK2, MGMT, SULT1E1 and SULT1A1 genes, genotyped in a total of 1597 cases and 1507 controls from two case-control studies, the Australian National Endometrial Cancer Study and the Polish Endometrial Cancer Study, were assessed for association with endometrial cancer risk using logistic regression analysis. Imputed data was drawn for CHEK2 rs8135424 for 666 cases from the Study of Epidemiology and Risk factors in Cancer Heredity study and 5190 controls from the Wellcome Trust Case Control Consortium. We observed no association between SNPs in the MGMT, SULT1E1 and SULT1A1 genes and endometrial cancer risk. The A allele of the rs8135424 CHEK2 SNP was associated with decreased risk of endometrial cancer (adjusted per-allele OR 0.83; 95%CI 0.70-0.98; p = .03) however this finding was opposite to that previously published. Imputed data for CHEK2 rs8135424 supported the direction of effect reported in this study (OR 0.85; 95% CI 0.65-1.10). Previously reported endometrial cancer risk associations with SNPs from in genes involved in estrogen metabolism and DNA repair were not replicated in our larger study population. This study highlights the need for replication of candidate gene SNP studies using large sample groups, to confirm risk associations and better prioritize downstream studies to assess the causal relationship between genetic variants and cancer risk. Our findings suggest that the CHEK2 SNP rs8135424 be prioritized for further study as a genetic factor associated with risk of endometrial cancer.
据报道，DNA修复和激素途径候选基因中的几种单核苷酸多态性（SNP）与子宫内膜癌风险相关。我们试图在两个子宫内膜癌病例对照样本集中证实这些关联，并利用现有全基因组关联研究的额外数据，优先选择一个额外的SNP进行进一步研究。在两项病例对照研究（澳大利亚国家子宫内膜癌研究和波兰子宫内膜癌研究）的总共1597例病例和1507例对照中，对来自CHEK2、MGMT、SULT1E1和SULT1A1基因的5个SNP进行基因分型，使用逻辑回归分析评估其与子宫内膜癌风险的关联。从癌症遗传流行病学和风险因素研究中为666例病例以及从威康信托病例对照联合体中为5190例对照提取了CHEK2 rs8135424的推断数据。我们未观察到MGMT、SULT1E1和SULT1A1基因中的SNP与子宫内膜癌风险之间存在关联。CHEK2 SNP rs8135424的A等位基因与子宫内膜癌风险降低相关（调整后的等位基因比值比为0.83；95%置信区间为0.70 - 0.98；p = 0.03），然而这一发现与先前发表的结果相反。CHEK2 rs8135424的推断数据支持了本研究报告的效应方向（比值比为0.85；95%置信区间为0.65 - 1.10）。先前报道的子宫内膜癌风险与参与雌激素代谢和DNA修复的基因中的SNP之间的关联在我们更大的研究人群中未得到重复验证。本研究强调了使用大样本组重复候选基因SNP研究的必要性，以确认风险关联，并更好地优先进行下游研究，以评估基因变异与癌症风险之间的因果关系。我们的研究结果表明，CHEK2 SNP rs8135424作为与子宫内膜癌风险相关的遗传因素，应优先进行进一步研究。
