SNP-SNP interactions between dNTP supply enzymes and mismatch DNA repair in breast cancer.

The dNTP supply system genes RRM1, DCTD, TYMS, TK1 and DCK balance dNTP pools to avoid incorrect insertions of bases (i.e. DNA mismatches) and the DNA mismatch repair system genes MLH1 and MSH2 are involved in removing such mismatches. The objective of this study is to explore the possibility of interactions between these two systems, since greater mismatch production rates are expected to be more detrimental in cells that also have compromised mismatch removal rates. This conjecture was explored here specifically with respect to the development of breast cancer. More than 2400 breast cancer cases and controls are included in the Cancer Genetic Markers of Susceptibility (CGEMS) single nucleotide polymorphism (SNP) dataset. For each of these individuals, a total of 99 SNPs (69 dNTP supply SNPs and 30 mismatch repair SNPs) and 2070 SNP-SNP interactions between these two groups were evaluated for their effect on breast cancer using logistic regression to compute odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Of these, 12 SNPs had found statistically significant associations with breast cancer individually (Four of them to decrease risk and eight of them to increase risk) and 697 of 2070 two-way interactions were significant associated with the risk of breast cancer. Thus, our study suggests that mismatches contribute to the formation of breast cancer.