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Human Molecular Genetics Advance Access published online on May 10, 2006
Human Molecular Genetics, 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.
Received March 7, 2006
Revised April 28, 2006
Accepted April 28, 2006

Article

Caspase 9 Promoter Polymorphisms and Risk of Primary Lung Cancer

Jae Yong Park 1 *, Jung Min Park 2, Jin Sung Jang 3, Jin Eun Choi 2, Kyung Mee Kim 2, Sung Ick Cha 4, Chang Ho Kim 4, Young Mo Kang 4, Won Kee Lee 5, Sin Kam 5, Rang Woon Park 3, In San Kim 3, Jae-Tae Lee 6, and Tae Hoon Jung 4

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

* To whom correspondence should be addressed.
Jae Yong Park, E-mail: jaeyong{at}kyungpook.ac.kr


  Abstract

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 4 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 to the -1263 AA genotype or combined -1263 AA + AG genotype (adjusted OR = 0.64, 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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[Abstract] [Full Text] [PDF]


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