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Carcinogenesis Advance Access published online on January 3, 2008
Carcinogenesis, doi:10.1093/carcin/bgm284
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Association of single-nucleotide polymorphisms in the Cell Cycle genes with breast cancer in the British population

Kristy E. Driver1, Honglin Song1, Fabienne Lesueur1, Shahana Ahmed1, Nuno L. Barbosa-Morais2, Jonathan Tyrer1, Bruce A. J. Ponder2, Douglas F. Easton3, Paul D. P. Pharoah1, Alison M. Dunning1 and for the SEARCH Team1

1 CR-UK Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK
2 CR-UK Department of Oncology, University of Cambridge, Cancer Research Institute, Cambridge, UK
3 CR-UK Genetic Epidemiology Unit, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK

Using a large scale case-control study, we examined whether common single nucleotide polymorphisms (SNPs) within 13 genes involved in the cell cycle pathway are associated with breast cancer risk. 79 tag SNPs were used to evaluate 240 common SNPs found in the genes: CCND1, CCND2, CCND3, CCNE1, CDK2, CDK4, CDK6, CDKN1A, CDKNIB, CDKN2A/CDKN2B, CDKN2C and CDKN2D. These were genotyped in 2270 cases and 2280 controls from the SEARCH study. Tag SNPs showing evidence of statistically significant differences between cases and controls (p<0.1) were genotyped in a further 2200 cases and 2280 controls from the same population. This approach found evidence for breast cancer associated SNPs in four of the cell cycle genes: the cyclin CCNE1 rs997669 had an odds ratio (OR) [GG/AA] of 1.18 (95% Confidence Interval (CI) 1.04-1.34) p=0.003; the cyclin dependent kinase inhibitors: CDKN1A rs3176336: OR [TT/AA] = 1.25 (95% CI 1.11-1.42) p=0.0026; CDKN1B rs34330: OR [TT/CC] = 1.22 (95% CI 1.02-1.47) p=0.013 and the region of CDKN2A/2B rs3731239: OR [CC/TT] = 0.90 (95% CI 0.79-1.03) p=0.013 and rs3218005 OR [GG/AA] = 1.55 (95% CI 1.02-2.37) p=0.013 (p-values unadjusted for multiple testing). We were able to exclude the D-type cyclins, cyclin-dependent kinases, CDKN2C and CDKN2D from having any significantly associated risk with breast cancer in our study population. The combined effects of the cell cycle genes considered here provide evidence for a significant association with breast cancer risk in a global test (p-heterogeneity = 0.010, p-trend = 0.048). Further large scale studies are needed to confirm these results.

The SEARCH study team are currently: Jean Abraham, Shahana Ahmed, Antonis Antoniou, Caroline Baynes, Patrick Benusiglio, Fiona Blows, Arancha Cebrian, Don Conroy, Bridget Curzon, Gary Dew, Kristy Driver, Helen Field, Maya Ghoussaini, Patricia Harrington, Catherine Healey, Sue Irvine, Bolot Kalmyrzaev, Clare Jordan, Fabienne Lesueur, Craig Luccarini, Rebecca Mayes, Melanie Maranian, Jonathan Morrison, Hannah Munday, Barbara Perkins, Karen Pooley, Karen Redman, Serena Scollen, Danielle Shadforth, Mitul Shah, Anabel Simpson, Anne Stafford, Deborah Thompson, Jonathan Tyrer, Paula Smith and Judy West.

Received August 17, 2007; revised November 5, 2007; accepted December 1, 2007.


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