Carcinogenesis Advance Access originally published online on December 6, 2006
Carcinogenesis 2007 28(6):1197-1201; doi:10.1093/carcin/bgl242
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Associations of functional polymorphisms in cyclooxygenase-2 and platelet 12-lipoxygenase with risk of occurrence and advanced disease status of colorectal cancer
1 Department of Etiology and Carcinogenesis, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
2 Department of Abdominal Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
* To whom correspondence should be addressed. Tel: +86 10 67722460; Fax: +86 10 67722460; Email: dlin{at}public.bta.net.cn
Aberrant arachidonic acid metabolism by cyclooxygenase (COX)-2 and 12-lipoxygenase (LOX) has implicated in carcinogenesis. Genetic polymorphisms in COX-2 and 12-LOX might therefore affect susceptibility to colorectal cancer (CRC). To examine this hypothesis, genotypes of COX-2 –1290A>G, –1195G>A, –765G>C and 12-LOX 261Arg>Gln polymorphisms were determined in 1000 CRC patients and 1300 controls. Increased risk of developing CRC was associated with the COX-2 –1195GA [adjusted odds ratio (OR) = 1.24, 95% confidence interval (CI) = 1.00–1.54] and –1195AA (adjusted OR = 1.77, 95% CI = 1.38–2.25) genotypes compared with the –1195GG genotype. Similarly, the increased risk for CRC was also associated with the COX-2 –765GC genotype (adjusted OR = 1.73, 95% CI = 1.23–2.43) compared with the –765GG genotype. Consistent with the results of genotype analyses, the ORs for the A_1195-C_765-containing haplotypes were significantly higher than those for the G_1195-G_765-containing haplotypes (P < 0.01). Furthermore, the –1195A allele was further associated with advanced CRC, with adjusted ORs of Dukes D CRC against Dukes A CRC being 2.43 (95% CI = 1.15–4.97) and 2.66 (95% CI = 1.23–5.74) for the –1195GA and –1195AA genotypes, respectively. The increased risk of CRC was also associated with the 12-LOX 261Gln/Gln genotype compared with the Arg/Arg genotype (adjusted OR = 1.38, 95% CI = 1.09–1.74). Together, these observations indicate that inherited polymorphisms in arachidonic acid-metabolizing enzymes may confer susceptibility to CRC.
Abbreviations: CI, confidence interval; COX, cyclooxygenase; CRC, colorectal cancer; HETE, hydroxyeicosatetraenoic acid; LOX, lipoxygenase; NSAID, non-steroidal anti-inflammatory drug; OR, odds ratio; SNP, single-nucleotide polymorphism
These authors contribute equally to this work. Received September 17, 2006; revised November 27, 2006; accepted November 30, 2006.
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