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Human Molecular Genetics Advance Access originally published online on May 10, 2006
Human Molecular Genetics 2006 15(12):1963-1971; doi:10.1093/hmg/ddl119
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© 2006 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Caspase 9 promoter polymorphisms and risk of primary lung cancer

Jae Yong Park1,3,5,*, Jung Min Park1, Jin Sung Jang3, Jin Eun Choi1, Kyung Mee Kim1, Sung Ick Cha5, Chang Ho Kim5, Young Mo Kang5, Won Kee Lee4, Sin Kam4, Rang Woon Park3, In San Kim3, Jae-Tae Lee2 and Tae Hoon Jung5

1Cancer Research Institute and 2Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Dong-In 2Ga 101, Daegu, 700-412, Republic of Korea, 3Department of Biochemistry and 4Department of Preventive Medicine, School of Medicine, Kyungpook National University, Dong-In 2Ga 101, Daegu, 700-422, Republic of Korea and 5Department of Internal Medicine, Kyungpook National University Hospital, Samduk 2Ga 50, Daegu, 700-412, Republic of Korea

* To whom correspondence should be addressed. Tel: +82 534205536; Fax: +82 534262046; Email: jaeyong{at}kyungpook.ac.kr

Received March 7, 2006; Accepted April 28, 2006

Caspase-9 (CASP-9) is an initiator CASP in the apoptosome-driven apoptosis pathway and plays an important role in the development and progression of cancer. Polymorphisms in the promoter region of the CASP-9 gene may influence the promoter activity of this gene, thereby modulating susceptibility to lung cancer. To test this hypothesis, we examined the association of four polymorphisms [–1263A>G, –905T>G, –712C>T and –293_–275delCGTGAGGTCAGTGCGGGGA (–293del)] in the CASP-9 promoter with the risk of lung cancer in a Korean population. The CASP-9 genotypes were determined in 432 lung cancer patients and 432 healthy controls that were frequency-matched for age and gender. The –1263 GG genotype was associated with a significantly decreased risk of lung cancer compared with the –1263 AA genotype or combined –1263 AA+AG genotype [adjusted odds ratio (OR)=0.64, 95% confidence interval (95% CI)=0.42–0.98, P=0.04 and adjusted OR=0.67, 95% CI=0.46–0.97, P=0.01, respectively]. For the –712C>T polymorphism, individuals with at least one –712T allele were at a significantly increased risk of lung cancer compared with those harboring the –712 CC genotype (adjusted OR=1.42, 95% CI=1.06–1.89, P=0.02). Consistent with the results of genotype analyses, the –1263G/–712C (G-C) haplotype was associated with a significantly decreased risk of lung cancer [adjusted OR=0.59, 95% CI=0.47–0.75, P and Bonferroni corrected P (Pc)<0.001]. Moreover, the risk of lung cancer decreased in a dose-dependent manner as the number of the G-C haplotypes increased (adjusted OR=0.60, 95% CI=0.45–0.81, P=0.0007 and Pc=0.0014 for the G-C heterozygotes and adjusted OR=0.34, 95% CI=0.17–0.68, P=0.0023 and Pc=0.0046 for the G-C homozygotes; Ptrend<0.001). The promoter assay revealed the G-C haplotype to have a significantly higher promoter activity than the –1263G/–712T and –1263A/–712C haplotypes. These results suggest that CASP-9 promoter polymorphisms affect CASP-9 expression and contribute to genetic susceptibility to lung cancer.


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