Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk
Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk
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DOI：
10.1158/0008-5472.can-04-2149
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发表时间：
2005-05-01
期刊：
影响因子：
11.2
通讯作者：
Nagase, H
中科院分区：
文献类型：
--
作者：
Kimura, MT;Mori, T;Nagase, H
STK 15/Aurora-A是染色体分离和胞质分裂所必需的丝氨酸/苏氨酸激酶，被认为是小鼠和人类的癌症易感基因。Aurora-A中的两个编码单核苷酸多态性，91 T> A [苯丙氨酸/异亮氨酸（F/I）]和169 G> A [缬氨酸/异亮氨酸（V/I）]，产生了四种单倍型，91 T-169 G，91 A-169 G，91 T-169 A和91 A-169 A。我们通过对197例食管癌病例和146例对照进行基因分型，评估这些编码单核苷酸多态性与食管癌风险之间的关系。单倍型91 A-169 A（131/157）在癌症病例中的发生率在统计学上更高（比值比，3.1452; 95%置信区间，1.0258-9.6435）。然后分析四种亚型之间的功能差异，以揭示癌症风险的来源。与131/ V57相比，131/157和F31/157在体内和体外的激酶活性水平降低至15%和40%。我们考虑了激酶活性之间的差异，并将个体分为四类Aurora-A单倍型组合。与最常见的类别111相比，类别I具有57.5%或更低的激酶活性，并且具有显著更高的估计癌症风险（比值比，5.5328; 95%置信区间，1.8149-16.8671）。异常核形态，基因组不稳定性的特征，观察到30至40倍更频繁的人永生化成纤维细胞过表达131/157或F31/157相比，其他。此外，在I类癌症（纯合子91 T-169 A）中观察到的染色体不稳定性水平显著高于III类癌症（纯合子91 A-169 G）。这些结果表明，激酶活性较低的Aurora-A单倍型组合可能以隐性或显性方式诱导基因组不稳定性并增加食管癌风险。
STK15/Aurora-A is a serine/threonine kinase essential for chromosome segregation and cytokinesis, and is considered to be a cancer susceptibility gene in mice and humans. Two coding single nucleotide polymorphisms in Aurora-A, 91T > A [phenylalanine/isoleucine (F/I)] and 169G > A [valine/isoleucine (V/I)1, create four haplotypes, 91T-169G, 91A-169G, 91T-169A, and 91A-169A. We evaluated the association between these coding single nucleotide polymorphisms and esophageal cancer risk by genotyping 197 esophageal cancer cases and 146 controls. Haplotype 91A-169A (131/157) was observed to be statistically more frequent in cancer cases (odds ratio, 3.1452; 95% confidence interval, 1.0258-9.6435). Functional differences among the four isoforms were then analyzed to reveal the source of the cancer risk. Kinase activity levels of 131/157 and F31/157 were reduced to 15% and 40% compared with 131/ V57 in vivo and in vitro. We considered the differences between the kinase activities and divided individuals into four categories of Aurora-A haplotype combination. Category I had 57.5% or less kinase activity compared with the most common category, category 111, and had a significantly higher estimate cancer risk (odds ratio, 5.5328; 95% confidence interval, 1.8149-16.8671). Abnormal nuclear morphology, a characteristic of genomic instability, was observed to be 30 to 40 times more frequent in human immortalized fibroblast cells overexpressing 131/157 or F31/157 compared with the others. Furthermore, significantly higher levels of chromosomal instability were observed in cancers in category I (homozygote 91T-169A) than those in category III (homozygous 91A-169G). These results indicate that the less kinase active Aurora-A haplotype combinations might induce genomic instability and increase esophageal cancer risk either in a recessive or a dominant manner.