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Association of Cyclin D1 Genotype with Breast Cancer Risk and Survival

¹ Department of Medicine, Division of Internal Medicine, Center for Health Services Research, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine and VA TN Valley Geriatric Research, Education, and Clinical Center, Nashville, Tennessee and ² Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

Requests for reprints: Xiao Ou Shu, Vanderbilt University Center for Health Services Research, 6th Floor, Medical Center East, Nashville, TN 37232-8300. Phone: 615-936-0713; Fax: 615-936-1269. E-mail: xiao-ou.shu{at}vanderbilt.edu

Cyclin D1 (CCND1) is a key cell cycle regulatory protein that governs cell cycle progression from the G₁ to S phase. A common polymorphism (A870G) in exon 4 of the CCND1 gene produces an alternate transcript (transcript-b) that preferentially encodes a protein with enhanced cell transformation activity and possible prolonged half-life. We evaluated the association of CCND1 A870G polymorphism with breast cancer risk and survival in 1,130 breast cancer cases and 1,196 controls who participated in the Shanghai Breast Cancer Study. Approximately 81% of cases and 79% of controls carried the A allele at A870G of the CCND1 gene [odds ratio, 1.1; 95% confidence interval (95% CI), 0.9-1.4]. As lightly stronger but nonsignificant association was found for the A allele among younger women (odds ratio, 1.3; 95% CI, 0.9-1.8). However, this polymorphism seems to modify the effect of hormonal exposures on postmenopausal breast cancer, as the positive associations of postmenopausal breast cancer with body mass index (Pfor interaction = 0.02) and waist-to-hip ratios (P for interaction < 0.03; all Ps are two sided) were only observed among women who carry the A allele at A870G of the CCND1 gene. Following up with this cohort of patients for an average of 4.84 years, we found that the CCND1 A870G polymorphism was inversely associated with overall and disease-free survival, particularly among women with late stage or estrogen/progesterone receptor-negative breast cancer. The adjusted hazard ratios for disease-free survival associated with GA and AA genotypes were 0.94 (95% CI, 0.49-1.82) and 0.41 (95% CI, 0.19-0.91) for tumor-node-metastasis stage III to IV breast cancer, and 0.35 (95% CI, 0.15-0.80) and 0.32 (95% CI, 0.13-0.79) for estrogen/progesterone receptor-negative breast cancer. This study suggests that CCND1 A870G polymorphism may modify the postmenopausal breast cancer risk associated with hormonal exposure and predict survival after breast cancer diagnosis.

Key Words: cyclin d1 polymorphism • breast cancer • Chinese women • CCND1

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