PDF file, 96K, Table S1. Mass transitions and method statistics for the determination of serum one-carbon metabolites Table S2. Linear regression ratio of prediagnostic serum levels of one-carbon metabolites in relation to baseline characteristics and other lifestyle factors among control subjects Table S3. Conditional odds ratios (ORs) and 95% confidence intervals (CIs) of hepatocellular carcinoma in relation to prediagnostic serum levels of one-carbon metabolites Table S4. Spearman correlation coefficients between prediagnostic serum levels of one-carbon metabolites among control subjects (n = 631) Table S5. Odds ratios (ORs) and 95% confidence intervals (CIs) of hepatocellular carcinoma relation to prediagnostic serum levels of choline, methionine and pyridoxal phosphate by smoking status and alcohol consumption.
ARTICLE ABSTRACT
Background: Rats fed diets deficient in choline develop hepatocellular carcinoma. Tumor DNA from these animals is characteristically hypomethylated, suggesting that disruption of the one-carbon metabolism pathway is an underlying mechanism for hepatocarcinogenesis. Prospective studies in humans on circulating choline and other one-carbon metabolites and hepatocellular carcinoma risk have been lacking.Methods: We prospectively examined the association between prediagnostic serum concentrations of one-carbon metabolites including betaine, choline, cystathionine, homocysteine, methionine, 5-methyltetrahydrofolate (5-MTHF), pyridoxal-5-phosphate (PLP, the bioactive form of vitamin B6) and S-adenosylmethionine (SAM), and risk of developing hepatocellular carcinoma based on a nested case–control study of 297 incident cases and 631 matched controls from a cohort of 18,244 men in Shanghai, China. Logistic regression methods were used to calculate ORs and 95% confidence intervals (CI) adjusted for established risk factors for hepatocellular carcinoma.Results: Serum choline and PLP were associated with statistically significant reduced risk of hepatocellular carcinoma, whereas serum cystathionine, methionine, and SAM were associated with increased hepatocellular carcinoma risk (all Ptrend < 0.05). The inverse associations for hepatocellular carcinoma risk with choline and PLP remained statistically significant after adjusting for all potential confounders. The multivariate-adjusted ORs (95% CIs) for the highest versus lowest quintiles of serum choline and PLP were 0.35 (0.16–0.78; P = 0.010) and 0.44 (0.25–0.78; P = 0.005), respectively. There were no associations for hepatocellular carcinoma risk with 5-MTHF, betaine, or homocysteine.Conclusion: The inverse associations between choline and vitamin B6 and the risk of hepatocellular carcinoma development are novel and warrant further investigation.Impact: Identifying new modifiable factors for hepatocellular carcinoma prevention is warranted. Cancer Epidemiol Biomarkers Prev; 22(10); 1884–93. ©2013 AACR.
