Huang, Yongxu
(2017)
A prospective evaluation of pancreatic cancer risk in relation to dietary one-carbon metabolism-related nutrients, serum B6 vitamers and metabolites of the kynurenine pathway.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Pancreatic cancer is one of the most lethal human cancers. No effective long-term treatment is available and few risk factors have been identified for pancreatic cancer. Therefore, there is a critical need for identifying novel primary prevention targets. One-carbon metabolism-related nutrients such as vitamin B6 and choline play an important role in DNA synthesis and methylation. The availability of methyl groups in the one-carbon metabolism are associated with epigenetic events related to pancreatic carcinogenesis. In the first prospective cohort study of Singapore Chinese (271 pancreatic cancer cases), we found higher intake of vitamin B6 and choline were associated with reduced risk of pancreatic cancer. Compared with the lowest quartile, hazard ratios (HRs) and 95% confidence intervals (CIs) for the highest quartiles of vitamin B6 and choline were 0.52 (0.36, 0.74) (P for trend = 0.001) and 0.67 (0.48, 0.93) (P for trend = 0.04), respectively. There were no clear associations between the other one-carbon metabolism-related nutrients and pancreatic cancer risk. To further investigate the role of vitamin B6 in pancreatic cancer development, in the second case-control study nested within two prospective cohorts of Asian populations, a biomarker-based approach was used to evaluate the associations between B6 vitamers in serum and risk of developing pancreatic cancer. The main finding of the second study was an inverse association between serum pyridoxal-5’-phosphate (PLP), the active form of vitamin B6, and pancreatic cancer risk. Compared with PLP deficient individuals (<20 nmol/L), the odds ratio (OR) and 95% confidence interval for PLP greater than 52.4 nmol/L was 0.46 (0.23, 0.92) (P for trend = 0.048). The inverse association between serum PLP and pancreatic cancer risk lends further support on dietary findings of vitamin B6. In the third case-control study nested within the same two cohorts, we found higher ratios of metabolites of the kynurenine (Kyn) pathway, as biomarkers for intracellular functional status of PLP, were associated with reduced risk of pancreatic cancer. Compared with the lowest tertiles, the second and third tertiles of 3’-hydroxyanthranilic acid (HAA):3’-hydroxykynurenine (HK) ratio and HAA:Kyn ratio were associated with about 40% reduced risk of pancreatic cancer. In addition, we found that higher serum concentrations of HAA, an anti-inflammatory metabolite of the PLP-dependent Kyn pathway, were associated with reduced risk of pancreatic cancer. Compared with the lowest tertile, the ORs and 95%CIs for the second and third tertiles of HAA were 0.61 (0.38-0.97) and 0.63 (0.39-1.01), respectively (P for trend =0.04). In summary, the three studies suggested a protective role of vitamin B6 in pancreatic cancer development. The finding on HAA sheds light on the potential protective effect of vitamin B6 may be via one of the PLP-dependent metabolic pathways, such as the Kyn pathway. The specific mechanisms underlying the potential protective effect against pancreatic cancer warrant future studies. This research is relevant to public health because understanding the role of the inter-individual variability of dietary nutrients, such as vitamin B6, in the development of cancer, may lead to identification of individuals at high risk for pancreatic cancer, and the development of cancer prevention strategies for reduction of cancer incidence and mortality.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
24 February 2017 |
| Date Type: |
Publication |
| Defense Date: |
2 September 2016 |
| Approval Date: |
24 February 2017 |
| Submission Date: |
23 November 2016 |
| Access Restriction: |
5 year -- Restrict access to University of Pittsburgh for a period of 5 years. |
| Number of Pages: |
155 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Epidemiology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Pancreatic cancer, vitamin B6, one-carbon metabolism, risk factors, kynurenine, prospective studies |
| Date Deposited: |
24 Feb 2017 19:13 |
| Last Modified: |
01 Jan 2022 06:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/30376 |
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