RRC ID 1953
Author Kimura MT, Mori T, Conroy J, Nowak NJ, Satomi S, Tamai K, Nagase H.
Title Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk.
Journal Cancer Res.
Abstract 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)], 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 (I31/I57) 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 I31/I57 and F31/I57 were reduced to 15% and 40% compared with I31/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 III, and had a significantly higher estimated 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 I31/I57 or F31/I57 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.
Volume 65(9)
Pages 3548-54
Published 2005-5-1
DOI 10.1158/0008-5472.CAN-04-2149
PII 65/9/3548
PMID 15867347
PMC PMC2536656
MeSH Aurora Kinase A Aurora Kinases Carcinoma, Squamous Cell / enzymology Carcinoma, Squamous Cell / genetics* Case-Control Studies Cell Nucleus / enzymology Chromosome Aberrations DNA, Neoplasm / genetics Esophageal Neoplasms / enzymology Esophageal Neoplasms / genetics* Gene Dosage Genetic Predisposition to Disease Haplotypes Humans Isoenzymes Polymorphism, Single Nucleotide Protein-Serine-Threonine Kinases / genetics* Protein-Serine-Threonine Kinases / metabolism Subcellular Fractions / enzymology
IF 8.378
Times Cited 48
Human and Animal Cells MRC-5 SV1 TG1