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Association Between Single-Nucleotide Polymorphisms in Hormone Metabolism and DNA Repair Genes and Epithelial Ovarian Cancer: Results from Two Australian Studies and an Additional Validation Set

¹ Queensland Institute of Medical Research; ² School of Population Health, University of Queensland, Brisbane, QLD, Australia; ³ Peter MacCallum Cancer Center, East Melbourne, Victoria, Australia; ⁴ Molecular, Environmental and Analytic Epidemiology, The University of Melbourne, Carlton, Victoria, Australia; ⁵ CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, United Kingdom; ⁶ Translational Research Laboratories, Institute for Women's Health, University College London, United Kingdom; ⁷ Institute of Cancer Epidemiology, Danish Cancer Society; ⁸ The Julianne Marie Center, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; ⁹ Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York; and ¹⁰ Department of Health Research and Policy, Stanford University School of Medicine, Palo Alto, California

Requests for reprints: G. Chenevix-Trench, Division of Cancer and Cell Biology, Queensland Institute of Medical Research, c/o Royal Brisbane Hospital Post Office, Herston, Queensland 4029, Australia. Phone: 617-3362-0390; Fax: 61-7-3362-0105. E-mail: georgiaT{at}qimr.edu.au

Although some high-risk ovarian cancer genes have been identified, it is likely that common low penetrance alleles exist that confer some increase in ovarian cancer risk. We have genotyped nine putative functional single-nucleotide polymorphisms (SNP) in genes involved in steroid hormone synthesis (SRD5A2, CYP19A1, HSB17B1, and HSD17B4) and DNA repair (XRCC2, XRCC3, BRCA2, and RAD52) using two Australian ovarian cancer case-control studies, comprising a total of 1,466 cases and 1,821 controls of Caucasian origin. Genotype frequencies in cases and controls were compared using logistic regression. The only SNP we found to be associated with ovarian cancer risk in both of these two studies was SRD5A2 V89L (rs523349), which showed a significant trend of increasing risk per rare allele (P = 0.00002). We then genotyped another SNP in this gene (rs632148; r² = 0.945 with V89L) in an attempt to validate this finding in an independent set of 1,479 cases and 2,452 controls from United Kingdom, United States, and Denmark. There was no association between rs632148 and ovarian cancer risk in the validation samples, and overall, there was no significant heterogeneity between the results of the five studies. Further analyses of SNPs in this gene are therefore warranted to determine whether SRD5A2 plays a role in ovarian cancer predisposition. (Cancer Epidemiol Biomarkers Prev 2007;16(12):2557–9)