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Two functional coding single nucleotide polymorphisms in STK15 (Aurora-A) coordinately increase esophageal cancer
Makoto T Kimura1, Takahiro Mori, Jeffrey Conroy
1Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
Cancer Research
|May 4, 2005
Summary
Reduced kinase activity of Aurora-A (STK15) haplotypes is linked to increased esophageal cancer risk. Specific Aurora-A variants, with lower kinase function, correlate with genomic instability and higher cancer incidence.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Oncology
Background:
- Aurora-A (STK15) is a key kinase in cell division and a known cancer susceptibility gene.
- Genetic variations, specifically single nucleotide polymorphisms (SNPs), in Aurora-A can alter protein function.
- Understanding these genetic variations is crucial for identifying cancer risk factors.
Purpose of the Study:
- To investigate the association between Aurora-A coding SNPs and haplotypes and esophageal cancer risk.
- To analyze the functional impact of different Aurora-A isoforms on kinase activity and cellular processes.
- To determine if reduced kinase activity of Aurora-A variants contributes to genomic instability and cancer development.
Main Methods:
- Genotyping of two Aurora-A SNPs (91T>A and 169G>A) in 197 esophageal cancer cases and 146 controls.
- Haplotype analysis to identify common and rare variants.
- In vitro and in vivo assays to measure kinase activity of different Aurora-A isoforms.
- Microscopy to assess nuclear morphology and chromosomal instability in cells expressing different Aurora-A variants.
Main Results:
- The 91A-169A (I31/I57) haplotype was significantly more frequent in esophageal cancer cases (OR, 3.1452).
- Aurora-A isoforms I31/I57 and F31/I57 exhibited significantly reduced kinase activity (15% and 40%) compared to I31/V57.
- Individuals with lower kinase activity (Category I) showed a substantially higher cancer risk (OR, 5.5328) and increased abnormal nuclear morphology.
- Higher chromosomal instability was observed in cancers with specific low-activity haplotypes.
Conclusions:
- Certain Aurora-A haplotype combinations with reduced kinase activity are associated with an increased risk of esophageal cancer.
- These less active Aurora-A variants may promote genomic instability, contributing to cancer development.
- The findings suggest a mechanism where impaired Aurora-A function increases susceptibility to esophageal cancer.