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Effects of Common Germ-Line Genetic Variation in Cell Cycle Genes on Ovarian Cancer Survival

Authors' Affiliations: ¹ CR-UK Department of Oncology and ² CR-UK Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory; ³ Eastern Cancer Registration and Information Centre (ECRIC), Cambridge, United Kingdom; ⁴ Department of Viruses, Hormones, and Cancer, Institute of Cancer Epidemiology, Danish Cancer Society; ⁵ University of Copenhagen, Copenhagen, Denmark; ⁶ Translational Research Laboratory, Department of Gynaecological Oncology, University College London, London, United Kingdom; ⁷ Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York; and ⁸ Department of Health Research and Policy, Stanford University School of Medicine, Stanford, California

Requests for reprints: Honglin Song, CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, United Kingdom. Phone: 44-1223-740161; Fax: 44-1223-740147; E-mail: honglin{at}srl.cam.ac.uk.

Purpose: Somatic alterations have been shown to correlate with ovarian cancer prognosis and survival, but less is known about the effects on survival of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division and could plausibly influence clinical characteristics of multiple tumors types.

Experimental Design: We examined associations between common germ-line genetic variation in 14 genes involved in cell cycle pathway (CCND1, CCND2, CCND3, CCNE1, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, CDKN2D, CDK2, CDK4, CDK6, and RB1) and survival among women with invasive ovarian cancer participating in a multicenter case-control study from United Kingdom, Denmark, and United States. DNAs from up to 1,499 women were genotyped for 97 single-nucleotide polymorphisms that tagged the known common variants (minor allele frequency 0.05) in these genes. The genotypes of each polymorphism were tested for association with survival by Cox regression analysis.

Results: A nominally statistically significant association between genotype and ovarian cancer survival was observed for polymorphisms in CCND2 and CCNE1. The per-allele hazard ratios (95% confidence intervals) were 1.16 (1.03-1.31; P = 0.02) for rs3217933, 1.14 (1.02-1.27; P = 0.024) for rs3217901, and 0.85 (0.73-1.00; P = 0.043) for rs3217862 in CCND2 and 1.39 (1.04-1.85; P = 0.033) for rs3218038 in CCNE1. However, these were not significant after adjusting for multiple hypothesis tests.

Conclusion: It is unlikely that common variants in cell cycle pathways examined above associated with moderate effect in survival after diagnosis of ovarian cancer. Much larger studies will be needed to exclude common variants with small effects.