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Death Receptor 4 Variants and Colorectal Cancer Risk

Divisions of ¹ Molecular Genetic Epidemiology, ² Clinical Epidemiology, and ³ Clinical Epidemiology and Aging Research and ⁴ Helmholtz-University Group Molecular Epidemiology, German Cancer Research Center, Heidelberg, Germany; ⁵ Department of Epidemiology, German Centre for Research on Ageing, Heidelberg, Germany; and ⁶ Center for Family Medicine, Karolinska Institute, Huddinge, Sweden

Requests for reprints: Bernd Frank, Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany. Phone: 49-6221-421461; Fax: 49-6221-421455. E-mail: b.frank{at}dkfz.de

The tumor necrosis factor–related apoptosis-inducing ligand receptor modulates apoptotic response by binding to the proapoptotic death receptor 4 (DR4). Perturbed apoptosis due to missense alterations in the candidate tumor suppressor gene DR4 leads to deregulated cell proliferation and cancer predisposition. Recent studies have discussed the association of DR4 variants with cancer risk. We evaluated, for the first time, the role of the Thr²⁰⁹Arg (626C>G) and Glu²²⁸Ala (683A>C) polymorphisms on colorectal cancer risk by genotyping 659 incident cases and 607 healthy controls drawn from the German population-based Darmkrebs: Chancen der Verhütung durch Screening (DACHS) study. Whereas DR4 Glu²²⁸Ala was not associated with colorectal cancer, Thr²⁰⁹Arg heterozygotes were at a significantly decreased colorectal cancer risk [odds ratio (OR), 0.73; 95% confidence interval (95% CI), 0.54-0.97]. Stratification according to sex and age exhibited a significant association of Thr²⁰⁹Arg with a decreased risk for male heterozygotes (OR, 0.68; 95% CI, 0.46-0.99) and for Arg²⁰⁹ carriers 65 years of age (OR, 0.65; 95% CI, 0.46-0.92) as well as an enhanced risk for female Ala²²⁸ carriers in a allele dose-dependent manner (P_trend = 0.01). Subsite analysis revealed a protective effect of Thr²⁰⁹Arg for rectal cancer risk (OR, 0.67; 95% CI, 0.48-0.95) and a significant risk increase for Ala²²⁸ carriers with advanced colorectal cancer stages (P_trend = 0.04). Haplotype analysis revealed a 2.4-fold risk for carriers of the rare 626C-683C haplotype (1% prevalence in the general population; OR, 2.37; 95% CI, 0.98-5.76). The score statistic yielded an empirical P of 0.03 of the haplotype-specific test for 626C-683C based on 20,000 simulations, suggesting that DR4 626C-683C may affect colorectal cancer predisposition. (Cancer Epidemiol Biomarkers Prev 2006;15(10):2002–5)

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