Tagging single nucleotide polymorphisms in cell cycle control genes and susceptibility to invasive epithelial ovarian cancer

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...

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Published in:	Cancer research (Chicago, Ill.) Vol. 67; no. 7; pp. 3027 - 3035
Main Authors:	GAYTHER, Simon A, HONGLIN SONG, BLACKER, Jan, DICIOCCIO, Richard, MCGUIRE, Valerie, WEBB, Penelope M, BEESLEY, Jonathan, GREEN, Adele C, WHITEMAN, David C, GOODMAN, Marc T, LURIE, Galina, CARNEY, Michael E, RAMUS, Susan J, MODUGNO, Francesmary, NESS, Roberta B, EDWARDS, Robert P, MOYSICH, Kirsten B, GOODE, Ellen L, COUCH, Fergus J, CUNNINGHAM, Julie M, SELLERS, Thomas A, WU, Anna H, PIKE, Malcolm C, KRUGER KJAER, Susan, IVERSEN, Edwin S, MARKS, Jeffrey R, GARCIA-CLOSAS, Montserrat, BRINTON, Louise, LISSOWSKA, Jolanta, PEPLONSKA, Beata, EASTON, Douglas F, JACOBS, Ian, PONDER, Bruce A. J, SCHILDKRAUT, Joellen, WHITTEMORE, Alice S, PEARCE, C. Leigh, CHENEVIX-TRENCH, Georgia, BERCHUCK, Andrew, PHAROAH, Paul D. P, QUAYE, Lydia, TYRER, Jonathan, SHADFORTH, Danielle, HOGDALL, Estrid, HOGDALL, Claus
Format:	Journal Article
Language:	English
Published:	Philadelphia, PA American Association for Cancer Research 01-04-2007
Subjects:	Antineoplastic agents Biological and medical sciences Case-Control Studies Cell Cycle - genetics Cell Cycle Proteins - genetics Cyclin-Dependent Kinases - genetics Cyclins - genetics Female Female genital diseases Genes, cdc Genetic Predisposition to Disease Gynecology. Andrology. Obstetrics Humans Medical sciences Ovarian Neoplasms - genetics Ovarian Neoplasms - pathology Pharmacology. Drug treatments Polymorphism, Single Nucleotide Tumors Ovarian diseases Ovary carcinoma Gene Ovary cancer Cell cycle Risk factor Tagging Genetics Malignant tumor Single nucleotide polymorphism Infiltrating tumor Female genital diseases
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Summary:	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 ( approximately 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 ( approximately 2,000 cases and approximately 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0008-5472 1538-7445
DOI:	10.1158/0008-5472.can-06-3261