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Tagging Single Nucleotide Polymorphisms in Cell Cycle Control Genes and Susceptibility to Invasive Epithelial Ovarian Cancer

¹ Translational Research Laboratories, University College London, London, United Kingdom; ² Cancer Research United Kingdom Department of Oncology and ³ Cancer Research United Kingdom Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom; ⁴ Danish Cancer Society, Copenhagen, Denmark; ⁵ Stanford University School of Medicine, Stanford, California; ⁶ University of Copenhagen, Copenhagen, Denmark; ⁷ Aarhus University Hospital, Skejby, Aarhus, Denmark; ⁸ Roswell Park Cancer Institute, Buffalo, New York; ⁹ The Queensland Institute of Medical Research, Post Office Royal Brisbane Hospital, Australia; ¹⁰ Cancer Research Center, University of Hawaii, Honolulu, Hawaii; ¹¹ Department of Epidemiology and University of Pittsburgh Cancer Institute, ¹² Department of Obstetrics, Gynecology and Reproductive Health, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; ¹³ Mayo Clinic College of Medicine, Rochester, Minnesota; ¹⁴ H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida; ¹⁵ University of Southern California, Keck School of Medicine, Los Angeles, California; ¹⁶ Duke University Medical Center, Durham, North Carolina; ¹⁷ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; ¹⁸ Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Institute of Oncology and Cancer Center, Warsaw, Poland; ¹⁹ Nofer Institute of Occupational Medicine, Lodz, Poland; and ²⁰ Peter MacCallum Cancer Institute, Melbourne, Australia

Requests for reprints: Simon Gayther, Translational Research Laboratories, Windeyer Institute, University College London, 46 Cleveland Street, London W1T 4JF, United Kingdom. Phone: 44-20-7679-9204; Fax: 44-20-7679-9687; E-mail: s.gayther{at}ucl.ac.uk.

High-risk susceptibility genes explain <40% of the excess risk of familial ovarian cancer. Therefore, other ovarian cancer susceptibility genes are likely to exist. We have used a single nucleotide polymorphism (SNP)–tagging approach to evaluate common variants in 13 genes involved in cell cycle control—CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKN1B, CDKN2A, CDKN2B, CDKN2C, and CDKN2D—and risk of invasive epithelial ovarian cancer. We used a two-stage, multicenter, case-control study. In stage 1, 88 SNPs that tag common variation in these genes were genotyped in three studies from the United Kingdom, United States, and Denmark (1,500 cases and 2,500 controls). Genotype frequencies in cases and controls were compared using logistic regression. In stage 2, eight other studies from Australia, Poland, and the United States (2,000 cases and 3,200 controls) were genotyped for the five most significant SNPs from stage 1. No SNP was significant in the stage 2 data alone. Using the combined stages 1 and 2 data set, CDKN2A rs3731257 and CDKN1B rs2066827 were associated with disease risk (unadjusted P trend = 0.008 and 0.036, respectively), but these were not significant after adjusting for multiple testing. Carrying the minor allele of these SNPs was found to be associated with reduced risk [OR, 0.91 (0.85–0.98) for rs3731257; and OR, 0.93 (0.87–0.995) for rs2066827]. In conclusion, we have found evidence that a single tagged SNP in both the CDKN2A and CDKN1B genes may be associated with reduced ovarian cancer risk. This study highlights the need for multicenter collaborations for genetic association studies. [Cancer Res 2007;67(7):3027–35]

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