Breast cancer is the most common cancer among women in the United States.
Nutrients in one-carbon metabolism (OCM) have been examined as potential modifiable
risk factors because of OCM’s important role in DNA methylation and DNA synthesis.
However, biologic mechanisms between OCM and carcinogenesis are still not clarified.
The first manuscript tested the hypothesis that OCM nutrient status and genetic
variation in methionine adenosyltransferases (MAT1A, MAT2A and MAT2B) are
associated with plasma S-adenosylmethionine (SAM) levels in a cross-sectional analysis
among healthy Singapore Chinese adults. Choline and methionine were strongly and
positively associated with plasma SAM levels (ptrend<0.0001), and folate and betaine
were positively associated with plasma SAM only in men (ptrend=0.02). The association
between MAT1A rs2993763 and plasma SAM was modified by gender and plasma methionine levels. In the same study population, the second manuscript cross-sectionally tested the
hypothesis that plasma SAM levels alone or in combination with genetic variation in
DNA methyltransferases (DNMT1, DNMT3A and DNMT3B) are associated with global
DNA methylation measured at long interspersed nucleotide element-1 (LINE-1). The
LINE-1 methylation index was positively associated with plasma SAM levels (p≤0.01),
with a plateau at approximately 78% and 77% methylation in men and women,
respectively. Among men, there were statistically significant positive or negative
associations between DNMT1 rs2114724 or DNMT3A rs758127 genotype and the LINE 1 methylation index, respectively (ptrend<0.01). The SAM-LINE-1 methylation
association was modulated by DNMT1 rs2114724 genotype in men only.
In a prospective cohort study, the third manuscript attempted to replicate
increased breast cancer risk related to higher dietary nitrate intake only among those with
low folate intake, which was previously reported by a case-control study. Opposite my
hypothesis, among women with total folate intake 400 μg/day or above, breast cancer risk
was statistically significantly higher among women in the highest quintile of nitrate
intake from public water (HR=1.40, 95%CI=1.05-1.87) and private well users (HR=1.38, 95%CI=1.05-1.82) than those with the lowest nitrate intake from public water.
The projects described in this dissertation contribute evidence describing how
OCM may be related to cancer risk, and are a step in pursuit of my long-term goal to
enhance our understanding of cancer etiology through OCM.