Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene:: a meta-analysis of multiple cancer types
Aurora-A/STK15 T+91A is a general low penetrance cancer susceptibility gene:: a meta-analysis of multiple cancer types
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DOI：
10.1093/carcin/bgi085
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发表时间：
2005-08-01
期刊：
影响因子：
4.7
通讯作者：
Balmain, A
中科院分区：
文献类型：
--
作者：
Ewart-Toland, A;Dai, Q;Balmain, A
STK15 (Aurora-A) 是一种参与有丝分裂染色体分离的丝氨酸/苏氨酸激酶。 STK15 T+91A 的遗传变异（导致氨基酸取代 F31I）与结肠肿瘤非整倍性增加和体外细胞转化相关。由于这种多态性在有丝分裂控制（对所有癌症类型至关重要的过程）中发挥作用，我们对 10 个独立的病例对照人群中的结肠癌、乳腺癌、前列腺癌、皮肤癌、肺癌和食道癌的发生风险进行了关联分析。我们对这 10 项病例对照研究以及另外 5 项已发表的研究进行了荟萃分析，涉及总共 9549 例乳腺癌、结肠癌、卵巢癌、前列腺癌、肺癌、食道癌和非黑色素瘤皮肤癌病例以及 8326 例人群或医院对照。三项结直肠癌研究的荟萃分析显示，T+91A 纯合子的风险增加（OR = 1.50；95% CI 1.14-1.99）。四项乳腺癌研究的荟萃分析显示，T+91A 纯合子的风险增加（OR = 1.35，95% CI 1.12-1.64）。所有 15 项研究的多癌症类型荟萃分析结果对于纯合子和杂合子的癌症风险都很重要。 T+91A 杂合子的癌症风险 OR 为 1.10（95% CI 1.03-1.18，P 值 = 0.006），T+91A 纯合子的癌症风险 OR 为 1.40（95% CI 1.22-1.59，P 值 < 0.001）。这些结果证实STK15 T+91A变异是一种影响多种癌症类型的低外显率癌症易感性等位基因，并提供了大规模人群研究的遗传证据，表明染色体水平的遗传稳定性是癌症易感性的重要决定因素。这些数据还强调了涉及不同种族群体的研究人群的比较关联研究在确定疾病风险方面的优势。
STK15 (Aurora-A) is a serine/threonine kinase involved in mitotic chromosomal segregation. A genetic variant in STK15 T+91A (resulting in the amino acid substitution F31I) is associated with increased aneuploidy in colon tumors and cell transformation in vitro. Since this polymorphism plays a role in mitotic control-a process critical for all cancer types-we conducted association analyses for risk of cancer development of the colon, breast, prostate, skin, lung and esophagus in 10 independent case-control populations. We carried out a meta-analysis of these 10 case-control studies together with 5 additional published studies for a total of 9549 cases of breast, colon, ovarian, prostate, lung, esophageal and non-melanoma skin cancer and 8326 population or hospital-based controls. Meta-analysis of three colorectal cancer studies showed an increased risk in T+91A homozygotes (OR = 1.50; 95% CI of 1.14-1.99). Meta-analysis of four breast cancer studies showed increased risk for T+91A homozygotes (OR = 1.35, 95% CI of 1.12-1.64). The results of the multiple cancer type meta-analysis for all 15 studies combined were significant for cancer risk in both homozygotes and heterozygotes. The T+91A heterozygotes show an OR of 1.10 (95% CI of 1.03-1.18, P-value = 0.006) and the T+91A homozygotes show an OR of 1.40 (95% CI of 1.22-1.59, P-value < 0.001) for cancer risk. These results confirm that the STK15 T+91A variant is a low penetrance cancer susceptibility allele affecting multiple cancer types, and provide genetic evidence from large-scale human population studies that genetic stability at the chromosome level is an important determinant of cancer susceptibility. The data also underline the advantages of comparative association studies involving study populations from different ethnic groups for determination of disease risk.