SNP-SNP interactions in breast cancer susceptibility

doi:10.1186/1471-2407-6-114

BMC Cancer

Volume 6

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Onay VÜ
Briollais L
Knight JA
Shi E
Wang Y
Wells S
Li H
Rajendram I
Andrulis IL
Ozcelik H

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Briollais L
Knight JA
Shi E
Wang Y
Wells S
Li H
Rajendram I
Andrulis IL
Ozcelik H
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Research article

SNP-SNP interactions in breast cancer susceptibility

Venüs Ümmiye Onay¹^,3 , Laurent Briollais¹^,2^,5 , Julia A Knight¹^,2^,5 , Ellen Shi⁴ , Yuanyuan Wang¹^,2 , Sean Wells¹^,3 , Hong Li¹^,3 , Isaac Rajendram¹^,3 , Irene L Andrulis¹^,3^,4^,6^,7 and Hilmi Ozcelik¹^,3^,7

¹Fred A. Litwin Centre for Cancer Genetics, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

²Prosserman Centre for Health Research, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada

³Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada

⁴Ontario Cancer Genetics Network, Cancer Care Ontario, Toronto, Ontario, Canada

⁵Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada

⁶Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario, Canada

⁷Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

author email corresponding author email

BMC Cancer 2006, 6:114doi:10.1186/1471-2407-6-114


Published:	3 May 2006

Abstract

Background

Breast cancer predisposition genes identified to date (e.g., BRCA1 and BRCA2) are responsible for less than 5% of all breast cancer cases. Many studies have shown that the cancer risks associated with individual commonly occurring single nucleotide polymorphisms (SNPs) are incremental. However, polygenic models suggest that multiple commonly occurring low to modestly penetrant SNPs of cancer related genes might have a greater effect on a disease when considered in combination.

Methods

In an attempt to identify the breast cancer risk conferred by SNP interactions, we have studied 19 SNPs from genes involved in major cancer related pathways. All SNPs were genotyped by TaqMan 5'nuclease assay. The association between the case-control status and each individual SNP, measured by the odds ratio and its corresponding 95% confidence interval, was estimated using unconditional logistic regression models. At the second stage, two-way interactions were investigated using multivariate logistic models. The robustness of the interactions, which were observed among SNPs with stronger functional evidence, was assessed using a bootstrap approach, and correction for multiple testing based on the false discovery rate (FDR) principle.

Results

None of these SNPs contributed to breast cancer risk individually. However, we have demonstrated evidence for gene-gene (SNP-SNP) interaction among these SNPs, which were associated with increased breast cancer risk. Our study suggests cross talk between the SNPs of the DNA repair and immune system (XPD-[Lys751Gln] and IL10-[G(-1082)A]), cell cycle and estrogen metabolism (CCND1-[Pro241Pro] and COMT-[Met108/158Val]), cell cycle and DNA repair (BARD1-[Pro24Ser] and XPD-[Lys751Gln]), and within carcinogen metabolism (GSTP1-[Ile105Val] and COMT-[Met108/158Val]) pathways.

Conclusion

The importance of these pathways and their communication in breast cancer predisposition has been emphasized previously, but their biological interactions through SNPs have not been described. The strategy used here has the potential to identify complex biological links among breast cancer genes and processes. This will provide novel biological information, which will ultimately improve breast cancer risk management.