Lesley M Butler1, Erland Arning, Renwei Wang, Teodoro Bottiglieri, Sugantha Govindarajan, Yu-Tang Gao, Jian-Min Yuan. 1. Authors' Affiliations: Cancer Control and Population Sciences, University of Pittsburgh Cancer Institute; and Department of Epidemiology, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania; Institute of Metabolic Disease, Baylor Research Institute, Dallas, Texas; Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, California; and Department of Epidemiology, Shanghai Cancer Institute, Shanghai, PR China.
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.
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.
Authors: Igor P Pogribny; Sharon A Ross; Carolyn Wise; Marta Pogribna; Elisabeth A Jones; Volodymyr P Tryndyak; S Jill James; Yvonne P Dragan; Lionel A Poirier Journal: Mutat Res Date: 2005-09-06 Impact factor: 2.433
Authors: R K Ross; J M Yuan; M C Yu; G N Wogan; G S Qian; J T Tu; J D Groopman; Y T Gao; B E Henderson Journal: Lancet Date: 1992-04-18 Impact factor: 79.321
Authors: G S Qian; R K Ross; M C Yu; J M Yuan; Y T Gao; B E Henderson; G N Wogan; J D Groopman Journal: Cancer Epidemiol Biomarkers Prev Date: 1994 Jan-Feb Impact factor: 4.254
Authors: Miranda J Spratlen; Maria Grau-Perez; Jason G Umans; Joseph Yracheta; Lyle G Best; Kevin Francesconi; Walter Goessler; Teodoro Bottiglieri; Mary V Gamble; Shelley A Cole; Jinying Zhao; Ana Navas-Acien Journal: Environ Res Date: 2018-09-27 Impact factor: 6.498
Authors: Chih-Ching Yeh; Abhishek Goyal; Jing Shen; Hui-Chen Wu; Joshua A Strauss; Qiao Wang; Irina Gurvich; Rachael A Safyan; Gulam A Manji; Mary V Gamble; Abby B Siegel; Regina M Santella Journal: Ann Surg Oncol Date: 2017-06-07 Impact factor: 5.344
Authors: J L Roffman; L J Petruzzi; A S Tanner; H E Brown; H Eryilmaz; N F Ho; M Giegold; N J Silverstein; T Bottiglieri; D S Manoach; J W Smoller; D C Henderson; D C Goff Journal: Mol Psychiatry Date: 2017-03-14 Impact factor: 15.992
Authors: Samuel O Antwi; Jessica L Petrick; Peter T Campbell; Daniel A Norez; Victoria L Stevens; Linda M Liao; Lewis R Roberts; Tushar Patel; Katherine A McGlynn Journal: Int J Cancer Date: 2020-04-25 Impact factor: 7.316