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Carcinogenesis Advance Access published online on August 12, 2004
Carcinogenesis, doi:10.1093/carcin/bgh260
© 2004 by Oxford University Press
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Received June 2, 2004
Revised July 23, 2004
Accepted August 2, 2004

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk

Julie E. Goodman 1, Elise D. Bowman 2, Stephen J. Chanock 3, Anthony J. Alberg 4, Curtis C. Harris 2*

1 Laboratory of Human Carcinogensis, National Cancer Institute, Bethesda, MD 20892, USA; Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, MD 20892, USA
2 Laboratory of Human Carcinogensis, National Cancer Institute, Bethesda, MD 20892, USA
3 Advanced Technology Center, National Cancer Institute, Bethesda, MD 20892, USA
4 Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA

* To whom correspondence should be addressed. E-mail: harrisc{at}mail.nih.gov.


  Abstract

In human colon, arachidonic acid is metabolized primarily by cyclooxygenase (COX) and arachidonate lipoxygenase (ALOX) to bioactive lipids, which are implicated in colon cancer risk. Several polymorphisms in ALOX and COX genes have been identified, including G-1752A, G-1699A and Glu254Lys in ALOX5; Gln261Arg in ALOX12; Leu237Met and Val481Ile in COX1; and C-645T and Val511Ala in COX2. Because of the significant role of arachidonic acid metabolism in colon cancer, we hypothesized that these polymorphisms could influence susceptibility to colon cancer. We addressed this hypothesis in African Americans and Caucasians using colon cancer cases (n=293) and hospital-based (n=229) and population-based (n=304) control groups. Polymorphisms did not differ between the control groups (p>0.05), thus, they are combined for all analyses presented. ALOX5 Glu254Lys and COX2 C-645T and Val511Ala allele frequencies differed between Caucasians and African American controls (p<0.001). The ALOX5 -1752 and -1699 polymorphisms were in linkage disequilibrium (p<0.001) and associated with decreased risk in Caucasians in ALOX5 haplotype analyses (p=0.03). Furthermore, an inverse association was observed between A alleles at positions -1752 and -1699 of ALOX5 and colon cancer risk in Caucasians, but not in African Americans. Caucasians with A alleles at ALOX5 -1752 had a reduced odds of colon cancer versus those with G alleles, [Odds Ratio (OR) (GA vs. GG), 0.63; 95% Confidence Interval (CI), 0.39-1.01; OR (AA vs. GG), 0.33; 95% CI, 0.07-1.65, ptrend = 0.02]. Similar results were observed for ALOX5 G-1699A [OR (GA vs. GG), 0.59, 95% CI, 0.37-0.94; OR (AA vs. GG), 0.27, 95% CI, 0.06-1.32, ptrend = 0.01]. Statistically significant associations with colon cancer were not observed for the other polymorphisms investigated. We have shown for the first time that a haplotype containing ALOX5 G-1752A and G-1699A in a negative regulatory region of the promoter may influence colon cancer risk in Caucasians.

Keywords: ALOX; COX; colon cancer.
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