Britton Trabert

PhD, MS

NIH

Investigator

PLCO (Learn more about this study)

2016-0049

Nov 22, 2016

One carbon metabolism and endometrial cancer risk

One-carbon metabolism is integral to DNA and amino acid synthesis, as well as methylation. As these processes play a role in cellular growth and division, it is not surprising that metabolites and genetic variants for enzymes within the one carbon metabolism pathways are of great interest in cancer epidemiology. Folate (vitamin B9) and the non-protein amino acid, homocysteine, are arguably the most frequently studied metabolites. Homocysteine is an inflammatory biomarker that is associated with oxidative stress and protein damage via homocysteinylation. Folate deficiency will increase homocysteine concentrations, but levels of these biomarkers are also influenced by other B-vitamin availability (B2/riboflavin, B6/pyridoxine, and B12/cobalamin) and variants in genes such as that encoding 5,10-methylenetetrahydrofolate reductase (MTHFR).

There is increasing evidence that abnormal DNA methylation contributes to endometrial carcinogenesis, suggesting that one-carbon metabolism metabolites and enzymes may influence the development of endometrial cancer. The epidemiological data evaluating dietary contributions of one carbon metabolism-metabolites has been inconsistent and recent meta-analyses have not identified associations with common variants in the MTHFR gene. No prior studies have evaluated circulating levels of one-carbon metabolism metabolites and endometrial cancer risk.

The relationship between one-carbon metabolism and endometrial cancer may also be mediated by biologic pathways governed by nuclear factor kappa-B (NF-κB) transcription factors. NF-κB regulates pathways involved in cellular proliferation and apoptosis as a well as inflammation. Oxidative and endoplasmic reticulum stress, which can be an effect of excess homocysteine, as well as cytokines like tumor necrosis factor (TNF) and IL-6 can activate NF-κB mediated gene expression. Genes regulated by NF-κB include TNF, IL-6, COX-2, and possibly, p53. Circulating levels of IL6 and TNF-alpha have been associated with increased risk of endometrial cancer, including a recent study we conducted using a nested case-control study from PLCO [quartile 4 vs quartile 1 Odds Ratio (OR) and 95% confidence interval (CI): TNF-alpha: 2.43 (1.17-5.04), IL6: 3.18 (1.47-6.86)].

Most instruments used to measure diet or supplementation are inherently imperfect as they not only require recall and a large degree of effort from participants, but may also fail to account for an individuals’ unique metabolism. For this reason, we propose using serum measurements of one-carbon metabolism metabolites when looking at endometrial cancer risk. Serum markers better reflect individual bioavailability and metabolism of these metabolites. Thus we propose to measure one-carbon metabolism metabolites in serum in a nested case-control study of endometrial cancer within PLCO.

Primary Aim: To evaluate the association between circulating one carbon metabolites and endometrial cancer risk.

We hypothesize that inflammatory biomarker, homocysteine, will be positively associated with endometrial cancer risk. We hypothesize that one-carbon metabolism metabolites that mediate chromosomal stability and DNA methylation (e.g. folate, methionine, enzyme cofactors B2, B6, B12) will be inversely associated with endometrial cancer risk.

Secondary Aim: To evaluate associations between one carbon metabolism metabolites and previously measured inflammation biomarkers in the nuclear factor kappa B (NF-kB) pathway with endometrial cancer risk.