Date on Master's Thesis/Doctoral Dissertation

5-2012

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Epidemiology and Population Health

Committee Chair

Baumgartner, Richard N.

Author's Keywords

Breast cancer; Breast cancer survival; Folate pathway; MTRR; MTR; MTHFR; BHMT

Subject

Breast--Cancer--Genetic aspects

Abstract

Genes in folate metabolizing pathway are responsible for modulating key enzymes in folate metabolisms necessary for DNA synthesis and repair and influence DNA methylation. Irregularity in DNA methylation may modify tumor phenotype response to chemotherapy and abnormal DNA synthesis, and repair may lead to carcinogenesis. This dissertation project tested the hypothesis that the key genes in the folate metabolizing pathway, namely Methylenetetrahydrofolate reductase (MTHFR) , betaine-homocysteinemethyltransferase (BHMT) , 5-methyltetrahydrofolate-homocysteine (MTR), 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) , and serine hydroxymethyltransferase (SHMT1) and folate receptor 1 (FOLR1) influences all- cause and breast cancer-specific mortality and the association between the genes in the folate metabolizing pathway and breast cancer-specific survival is modified by chemotherapy and estrogen receptor (ER) status. Gene-gene interactions among the genes in the folate metabolizing pathway were also tested in this study. Data for this study were obtained from the New Mexico site of the Health, Eating, Activity, and Lifestyle (HEAL) Study for 446 incident primary breast cancer cases (stage 0 - IIIA). Over 11.46 years of follow-up, there were 67 deaths; 22 due to breast cancer. In the Cox proportional hazards analysis, women who carried at least one variant allele for MTRR G66A polymorphism had statistically significant inverse associations with all- cause (Hazard Ratio [HR]: 0.51; 95% confidence interval [CI]: 0.3-0.8; p-value < 0.01) and breast cancer-specific mortality (HR: 0.40; 95% CI: 0.2-0.9; p-value < 0.01). There were no statistically significant interactions with chemotherapy or ER status. Synergistic multiplicative interaction was observed between BHMT A742G and FOLR1 G606A polymorph isms in predicting breast cancer-specific mortality (p for interaction: 0.03). In this sample, there was antagonistic multiplicative interaction between MTRR G66A and MTHFR C677T polymorphisms in predicting breast cancer-specific mortality (p for interaction: 0.08). These results should be further explored in larger cohorts and in clinical populations.

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