Associations Between Genetic Polymorphisms in DNA Bypass Polymerases and Base Excision Repair Genes with the Risk of Breast Cancer Public Deposited

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  • March 21, 2019
Creator
  • Family, Leila
    • Affiliation: Gillings School of Global Public Health, Department of Epidemiology
Abstract
  • Background: Mutations in BRCA1, a DNA repair gene, have been associated with a lifetime increased risk of breast cancer. Therefore, researchers hypothesized there may be other DNA repair genes associated with breast cancer risk. However thus far, studies of common low-penetrant DNA repair SNPs have not yielded consistent results. In this proposed study, we hypothesized one or more of the following mechanisms may explain the lack of main SNP effects: combined SNP effects, modification by race or breast cancer subtype, and functional redundancy. Methods: To evaluate these hypotheses, we used genotype data from the Carolina Breast Cancer Study (1,972 cases and 1,776 controls) to investigate race-specific, subtype-specific, and combined SNP associations using unconditional logistic regression in two DNA damage pathways, base excision repair (BER) and translesion synthesis (TLS). For BER, we evaluated the association between 31 single-nucleotide polymorphisms (SNPs) in 15 genes and breast cancer risk. SKAT, a pathway-based analytic method, was used to evaluate the combined SNP effects within the BER pathway. Results: Among Whites, our results showed a significant positive association for NEIL2 rs1534862 and a significant inverse association for PCNA rs17352. Among African Americans, we found a suggestive positive association for UNGrs3219275 and an inverse association for NEIL2rs8191613. Tumor subtype analysis showed that NEIL2 rs1534862 was associated with luminal and HER2+/ER-negative subtypes. SKAT analysis showed no significant combined effects between SNPs. For DNA bypass polymerases, we evaluated the association between 22 single-nucleotide polymorphisms (SNPs) in 7 bypass polymerase genes and breast cancer risk. We found similar increased odds ratios for breast cancer with three POLQ SNPs (rs487848, rs532411, rs3218634), which were also in high LD in both races. Furthermore, analysis by specific tumor subtypes showed all three SNPs were associated with increased risk of luminal breast cancer. Conclusions: These significant findings need to be replicated independently in other studies. Overall, our results did not indicate associations with breast cancer, which may concur with the theory that our cells possess an intricate system of functionally redundant DNA repair mechanisms in order to avoid the catastrophic effects of genomic instability.
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  • In Copyright
Advisor
  • Olshan, Andrew
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill
Graduation year
  • 2014
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