Carcinogenesis Advance Access originally published online on July 8, 2009
Carcinogenesis 2009 30(9):1562-1570; doi:10.1093/carcin/bgp173
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Genetic susceptibility to the development and progression of breast cancer associated with polymorphism of cell cycle and ubiquitin ligase genes
Department of Surgery, Tri-Service General Hospital, Taipei 11472, Taiwan, Republic of China
1 Department of Nursing, Kang-Ning Junior College of Medical Care and Management, Taipei 11485, Taiwan, Republic of China
2 Genomic Research Center
3 Taiwan Biobank
4 Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, Republic of China
5 Department of Surgery, Changhua Christian Hospital, Changhua 50006, Taiwan, Republic of China
6 Department of Radiology, Tri-Service General Hospital, Taipei 11472, Taiwan, Republic of China
7 Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80761, Taiwan, Republic of China
8 Institute of Biochemistry and Biotechnology, Chung Shan Medical University, Taichung 40242, Taiwan, Republic of China
9 Graduate Institute of Environmental Science, China Medical University, Taichung 40402, Taiwan, Republic of China
* To whom correspondence should be addressed. Tel: +886 2 27899036; Fax: +886 2 27823047; Email: bmcys{at}ibms.sinica.edu.tw
Tumor levels of the cell cycle regulators cyclin E and p27 correlate strongly with survival in breast cancer patients and are specifically regulated by the ubiquitin ligases hCDC4 and SKP2. This study was to explore whether genetic susceptibility to breast cancer is associated with polymorphism of these genes and whether gene–gene and gene–risk factor [i.e. full-term pregnancy (FTP)] interactions are important in determining cancer risk. A two-stage case–control study based on single-nucleotide polymorphisms was performed. The first study (560 cases and 1122 controls) was to define the contribution of cell cycle and ubiquitin ligase genes to cancer susceptibility. The second study (926 cases and 923 controls) was to confirm the association identified in the first stage and to map the variant alleles. Increased breast cancer risk was associated with both polymorphism of hCDC4 and a joint effect of cyclin E and hCDC4. These associations were more significant in nulliparous women, and cancer risk associated with a lower number of FTPs was only seen in women with a higher number of high-risk genotypes, providing support for an effect of gene–risk factor interaction in determining susceptibility. Sequence variants of intron 2 in hCDC4 were found to be the most significant polymorphism and high-stage estrogen receptor (ER)-negative patients carrying the homozygous variant genotype manifested significantly poorer survival. This study concludes that polymorphism of hCDC4 is a risk factor for breast cancer development by interacting with either cyclin E or FTP and may also prove useful in predicting progression of patients with high-stage and ER-negative breast cancers.
Abbreviations: aOR, adjusted odds ratio; CI, confidence interval; CKI, cyclin-dependent kinase inhibitor; ER, estrogen receptor; FTP, full-term pregnancy; LD, linkage disequilibrium; SNP, single-nucleotide polymorphism
These authors contributed equally to this work. Received April 16, 2009; revised June 11, 2009; accepted July 4, 2009.