Carcinogenesis Advance Access originally published online on January 8, 2007
Carcinogenesis 2007 28(5):1079-1086; doi:10.1093/carcin/bgl256
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Breast cancer risk associated with genotypic polymorphism of the mitotic checkpoint genes: a multigenic study on cancer susceptibility
1 Institute of Biomedical Sciences
2 Life Science Library, Academia Sinica, Taipei 11529, Taiwan
3 Division of Biostatistics and Bioinformatics, National Health Research Institute, Chu-Nan 350, Taiwan
4 Department of Surgery
5 Department of Radiology, Tri-Service General Hospital, Taipei 114, Taiwan
6 Department of Surgery, Changhua Christian Hospital, Changhua 500, Taiwan
7 Graduate Institute of Environmental Science, China Medical University, Taichung 407, Taiwan
* To whom correspondence should be addressed. Tel: +886 2 2789 9036; Fax: +886 2 2782 3047; Email: bmcys{at}ibms.sinica.edu.tw
Aneuploidy occurs early during tumorigenesis and may contribute to tumor formation. Tumor cells become aneuploid as a result of aberrant mitotic divisions, suggesting a tumorigenic contribution of the mechanisms in maintaining chromosomal number stability. We therefore speculated that the genes TTK, MAD2L1, BUB1, BUB1B and PTTG1 (Securin), jointly implicated in the regulation of mitotic checkpoint, might be associated with breast tumorigenesis. To test this hypothesis, this case–control study of 698 primary breast cancer patients and 1492 healthy controls examined single-nucleotide polymorphisms (SNPs) in these mitotic checkpoint genes to define their tumorigenic contribution. Because estrogen is known to promote breast cancer development via its mitogenic effect leading to malignant proliferation of breast epithelium and the mitotic checkpoint genes are involved in regulating mitosis, we were also interested in knowing whether any association between genotypes and breast cancer risk was modified by reproductive risk factors. Support for these hypotheses came from the observations that (i) two SNPs in TTK and PTTG1 were associated with breast cancer risk; (ii) haplotype and haplotype combination analyses in TTK, BUB1B and PTTG1 revealed a strong association with breast cancer risk; (iii) a trend to an increased risk of breast cancer was found in women harboring a greater number of putative high-risk genotypes/haplotypes of mitotic checkpoint genes and (iv) a significant interaction between high-risk genotypes/haplotypes and reproductive risk factors in determining breast cancer risk was defined. This study provides new support for the mutator role of mitotic checkpoint genes in breast cancer development, suggesting that breast cancer could be driven by genomic instability associated with variant mitotic checkpoint genes, the tumorigenic contribution of which could be enhanced as a result of increased mitosis due to estrogen exposure.
Abbreviations: aOR, adjusted odds ratio; BMI, body mass index; CI, confidence interval; CIN, chromosomal instability; FFTP, first full-term pregnancy; FTP, full-term pregnancy; LD, linkage disequilibrium; OR, odds ratio; SNP, single-nucleotide polymorphism
Received September 27, 2006; revised November 26, 2006; accepted December 20, 2006.
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