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Carcinogenesis Advance Access published online on December 3, 2004
Carcinogenesis, doi:10.1093/carcin/bgh351
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Oxford University Press
Received September 28, 2004
Revised November 11, 2004
Accepted November 21, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Case-control analysis of thymidylate synthase polymorphisms and risk of lung cancer

Qiuling Shi 1, Zhengdong Zhang 1, Ana S. Neumann 1, Guojun Li 1, Margaret R. Spitz 1, and Qingyi Wei 1*

1 Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

* To whom correspondence should be addressed.
Qingyi Wei, E-mail: qwei{at}mdanderson.org


  Abstract

Although tobacco smoking is the primary risk factor for lung cancer, low dietary folate intake and suboptimal DNA repair capacity also contribute to lung cancer risk. Thymidylate synthase (TYMS) is involved in the metabolism of folate and the provision of nucleotides needed for DNA synthesis and repair. Thus, a variation in TYMS functions likely plays a role in the etiology of lung cancer. The TYMS gene has a tandem repeat polymorphism (two or three 28-bp) in the TYMS enhancer region (TSER) and a 6-bp deletion/insertion polymorphism in the TS 3' untranslated region (TS3'UTR, or 1494del6). We investigated the frequencies of these two polymorphisms in a hospital-based case-control study of 1,055 lung cancer patients and 1,140 cancer-free controls in a non-Hispanic white population and genotyped for these two polymorphisms. We found that the TS3'UTR, but not the TSER, variant was associated with the risk of lung cancer. Compared with homozygotes for the TS3'UTR 6-bp deletion (0 bp/0 bp), the 6 bp/0 bp+6 bp/6 bp genotypes were associated with a significantly increased risk of lung cancer (odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.12-2.06). In stratification analysis, the risk associated with the 0bp/6bp+6bp/6bp genotype was more pronounced in subjects who were older than 55 (OR = 1.57, 95% CI = 1.10-2.23), males (OR = 1.88, 95% CI = 1.22-2.89), current (OR = 2.04, 95% CI = 1.26-3.29) and heavy smokers (OR = 1.73, 95% CI = 1.10-2.70) and current drinkers (OR = 3.17, 95% CI = 1.78-5.64). Furthermore, significant gene-dietary interactions were found between TS3'UTR and alcohol consumption and between TSER and vitamin B12 intake. In conclusion, the polymorphisms of TYMS are likely to contribute to the risk of lung cancer in non-Hispanic whites and interact with dietary factors in lung cancer development.

Keywords: DNA repair; biomarker; folate metabolism; genetic susceptibility; molecular epidemiology; lung cancer.
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