Effects of common germline genetic variation in cell cycle control genes on breast cancer survival: results from a population-based cohort

Elizabeth M Azzato¹^,2 , Kristy E Driver¹ , Fabienne Lesueur¹ , Mitul Shah¹ , David Greenberg³ , Douglas F Easton⁴ , Andrew E Teschendorff⁵ , Carlos Caldas⁵ , Neil E Caporaso² and Paul DP Pharoah¹

¹Department of Oncology, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK

²Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Executive Plaza South, Rm 7002, 6120 Executive Blvd, Rockville, MD, 20852, USA

³Eastern Cancer Registration and Information Centre, Unit C-Magog Court, Shelford Bottom, Cambridge, CB22 3AD, UK

⁴Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, Strangeways Research Laboratory, Worts Causeway, Cambridge, CB1 8RN, UK

⁵Cancer Research UK, Cambridge Research Institute, and Department of Oncology, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge, CB2 0RE, UK

author email corresponding author email

Breast Cancer Research 2008, 10:R47doi:10.1186/bcr2100


Published:	28 May 2008

Abstract

Introduction

Somatic alterations have been shown to correlate with breast cancer prognosis and survival, but less is known about the effects of common inherited genetic variation. Of particular interest are genes involved in cell cycle pathways, which regulate cell division.

Methods

We examined associations between common germline genetic variation in 13 genes involved in cell cycle control (CCND1, CCND2, CCND3, CCNE1, CDK2 [p33], CDK4, CDK6, CDKN1A [p21, Cip1], CDKN1B [p27, Kip1], CDKN2A [p16], CDKN2B [p15], CDKN2C [p18], and CDKN2D [p19]) and survival among women diagnosed with invasive breast cancer participating in the SEARCH (Studies of Epidemiology and Risk factors in Cancer Heredity) breast cancer study. DNA from up to 4,470 women was genotyped for 85 polymorphisms that tag the known common polymorphisms (minor allele frequency > 0.05) in the genes. The genotypes of each polymorphism were tested for association with survival using Cox regression analysis.

Results

The rare allele of the tagging single nucleotide polymorphism (SNP) rs2479717 is associated with an increased risk of death (hazard ratio = 1.26 per rare allele carried, 95% confidence interval: 1.12 to 1.42; P = 0.0001), which was not attenuated after adjusting for tumour stage, grade, and treatment. This SNP is part of a large linkage disequilibrium block, which contains CCND3, BYSL, TRFP, USP49, C6ofr49, FRS3, and PGC. We evaluated the association of survival and somatic expression of these genes in breast tumours using expression microarray data from seven published datasets. Elevated expression of the C6orf49 transcript was associated with breast cancer survival, adding biological interest to the finding.

Conclusion

It is possible that CCND3 rs2479717, or another variant it tags, is associated with prognosis after a diagnosis of breast cancer. Further study is required to validate this finding.