Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer risk.
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.
Kimura
Makoto T
MT
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Mori
Takahiro
T
Conroy
Jeffrey
J
Nowak
Norma J
NJ
Satomi
Susumu
S
Tamai
Katsuyuki
K
Nagase
Hiroki
H
D064096:Aurora Kinase A; D064127:Aurora Kinases; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D002467:Cell Nucleus / Q000201:enzymology; D002869:Chromosome Aberrations; D004273:DNA, Neoplasm / Q000235:genetics; D004938:Esophageal Neoplasms / Q000201:enzymology / Q000235:genetics*; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D007527:Isoenzymes; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D013347:Subcellular Fractions / Q000201:enzymology
D004273:DNA, Neoplasm; D007527:Isoenzymes; C576917:AURKA protein, human; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases