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Cyclin D1 Pro²⁴¹Pro (CCND1-G870A) Polymorphism Is Associated with Increased Cancer Risk in Human Populations: A Meta-Analysis

¹ Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, ² Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, ³ Department of Laboratory Medicine and Pathobiology, University of Toronto; ⁴ Division of Hematology/Oncology, Hospital for Sick Children, and ⁵ Analytical Genetics Technology Centre, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada

Requests for reprints: Hilmi Ozcelik, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 60 Murray Street, Room L6-304, Box 29, Toronto, Ontario, Canada M5T 3L9. Phone: 416-586-4800, ext. 4996; Fax: 416-586-8869. E-mail: ozcelik{at}mshri.on.ca

The G870A polymorphism in the CCND1 gene may influence cancer risk. However, data from published studies with individual low statistical power have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and cancer, we considered all available studies in a meta-analysis. Sixty studies were combined representing data for 18,411 cases and 22,209 controls. In our meta-analysis, we investigated overall sample and two ethnic populations (Caucasians and Asians) as well as nine cancer subtypes. Individuals who are homozygous for A allele (AA) were found to be associated with significantly increased cancer risk in overall sample [odds ratio (OR), 1.23; 95% confidence interval (95% CI), 1.13-1.33; P 0.0001], Caucasians (OR, 1.16; 95% CI, 1.07-1.26; P = 0.0002), and Asians (OR, 1.26; 95% CI, 1.14-1.39; P 0.001). Among the nine cancer subtypes investigated, modestly significant risk (ORs, 1.08 to 1.51; P = 0.02 to 0.04) was detected in breast, colorectal, head and neck, and other cancers. Highly significant and increased risk was found to be associated with genitourinary (OR, 1.51; 95% CI, 1.20-1.89; P = 0.0004) and blood-related cancers (OR, 1.62; 95% CI, 1.28-2.05; P 0.0001). Individuals who are heterozygous for AG were found to be at increased risk in overall, ethnic groups, as well as breast and colorectal cancers. Significant dominant effects seem to prevail in the majority of the categories investigated, where some recessive effects were also detected. Overall, the risk effects associated with this polymorphism were small; however, due its common occurrence, it affects a large portion of the human population (AA, 25%; AG, 50%). Although the independent small risk associated with CCND1-A870G polymorphism is not clinically useful, its interaction with other genetic variants and environmental factors has been shown to be associated with further increase in cancer risk (OR, 1.6-7.1). In conclusion, our study strongly supports the increased cancer risk associated with CCND1-A870G polymorphism in the human population. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2773–81)

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