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SNP-SNP interactions between dNTP supply enzymes and mismatch DNA repair in breast cancer
I Jung Feng1, Tomas Radivoyevitch
1Department of epidemiology and Biostatistics, Case Western Reserve University, Cleveland Ohio, U.S.A.
Abstract:
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.
Insights
DNA mismatches and their repair impact breast cancer risk. This study found significant associations between dNTP supply, mismatch repair genes, and breast cancer development, suggesting mismatches contribute to cancer formation.
Area of Science:
- Genetics
- Cancer Biology
- Molecular Epidemiology
Background:
- The dNTP supply system (genes RRM1, DCTD, TYMS, TK1, DCK) maintains DNA base balance.
- The DNA mismatch repair system (genes MLH1, MSH2) corrects DNA base insertion errors.
- Interactions between these systems may influence cancer development, particularly breast cancer.
Purpose of the Study:
- To investigate potential interactions between dNTP supply and DNA mismatch repair systems in breast cancer.
- To assess the combined effect of genetic variations in these systems on breast cancer risk.
Main Methods:
- Utilized the Cancer Genetic Markers of Susceptibility (CGEMS) dataset with over 2400 breast cancer cases and controls.
- Analyzed 99 single nucleotide polymorphisms (SNPs) in dNTP supply and mismatch repair genes.
- Evaluated 2070 SNP-SNP interactions using logistic regression to determine odds ratios (ORs) and 95% confidence intervals (CIs).
Main Results:
- Twelve SNPs showed statistically significant individual associations with breast cancer risk (four decreasing, eight increasing).
- A significant number of two-way interactions (697 out of 2070) between dNTP supply and mismatch repair SNPs were associated with breast cancer risk.
- These findings highlight the complex interplay between DNA maintenance pathways and cancer susceptibility.
Conclusions:
- The study suggests that DNA mismatches play a role in the etiology of breast cancer.
- Interactions between the dNTP supply and DNA mismatch repair systems are critical factors in breast cancer development.
- Genetic variations in these pathways represent potential targets for understanding breast cancer susceptibility.
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