期刊
CANCER RESEARCH
卷 65, 期 9, 页码 3548-3554出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-04-2149
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资金
- NCI NIH HHS [P30 CA016056, CA16056] Funding Source: Medline
- NIEHS NIH HHS [R01 ES012249, ES012249-01, R01 ES012249-02, R01 ES012249-01A1] Funding Source: Medline
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.
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