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Serum folate concentrations at diagnosis are associated with hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort study

  • Ai-Ping Fang (a1) (a2), Zhao-Yan Liu (a1), Gong-Cheng Liao (a1), Pei-Yan Chen (a1), Xiao-Yan Wang (a1), Dao-Ming Zhang (a1), Yun Luo (a1), Jing-An Long (a1), Rong-Huan Zhong (a1), Zhong-Guo Zhou (a3) (a4), Yan-Jun Xu (a5), Xiao-Jun Xu (a5), Wen-Hua Ling (a1) (a2), Min-Shan Chen (a3) (a4), Yao-Jun Zhang (a3) (a4) and Hui-Lian Zhu (a1) (a2)...


Existing data on folate status and hepatocellular carcinoma (HCC) prognosis are scarce. We prospectively examined whether serum folate concentrations at diagnosis were associated with liver cancer-specific survival (LCSS) and overall survival (OS) among 982 patients with newly diagnosed, previously untreated HCC, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study between September 2013 and February 2017. Serum folate concentrations were measured using chemiluminescent microparticle immunoassay. Cox proportional hazards models were performed to estimate hazard ratios (HR) and 95 % CI by sex-specific quartile of serum folate. Compared with patients in the third quartile of serum folate, patients in the lowest quartile had significantly inferior LCSS (HR = 1·48; 95 % CI 1·05, 2·09) and OS (HR = 1·43; 95 % CI 1·03, 1·99) after adjustment for non-clinical and clinical prognostic factors. The associations were not significantly modified by sex, age at diagnosis, alcohol drinking status and Barcelona Clinic Liver Cancer (BCLC) stage. However, there were statistically significant interactions on both multiplicative and additive scale between serum folate and C-reactive protein (CRP) levels or smoking status and the associations of lower serum folate with worse LCSS and OS were only evident among patients with CRP > 3·0 mg/l or current smokers. An inverse association with LCSS were also observed among patients with liver damage score ≥3. These results suggest that lower serum folate concentrations at diagnosis are independently associated with worse HCC survival, most prominently among patients with systemic inflammation and current smokers. A future trial of folate supplementation seems to be promising in HCC patients with lower folate status.


Corresponding author

*Corresponding authors: Yao-Jun Zhang, email; Hui-Lian Zhu, email


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1. Torre, LA, Bray, F, Siegel, RL, et al. (2015) Global cancer statistics, 2012. CA Cancer J Clin 65, 87108.
2. Allemani, C, Matsuda, T, Di Carlo, V, et al. (2018) Global surveillance of trends in cancer survival 2000–14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet 391, 10231075.
3. Llovet, JM, Zucman-Rossi, J, Pikarsky, E, et al. (2016) Hepatocellular carcinoma. Nat Rev Dis Primers 2, 16018.
4. Bruix, J, Sherman, M, Llovet, JM, et al. (2001) Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. European Association for the Study of the Liver. J Hepatol 35, 421430.
5. Newman, AC & Maddocks, ODK (2017) One-carbon metabolism in cancer. Br J Cancer 116, 14991504.
6. Lamprecht, SA & Lipkin, M (2003) Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat Rev Cancer 3, 601614.
7. Hansen, MF, Jensen, SO, Fuchtbauer, EM, et al. (2017) High folic acid diet enhances tumour growth in PyMT-induced breast cancer. Br J Cancer 116, 752761.
8. Pogribny, IP, James, SJ & Beland, FA (2012) Molecular alterations in hepatocarcinogenesis induced by dietary methyl deficiency. Mol Nutr Food Res 56, 116125.
9. Lai, KG, Chen, CF, Ho, CT, et al. (2017) Novel roles of folic acid as redox regulator: modulation of reactive oxygen species sinker protein expression and maintenance of mitochondrial redox homeostasis on hepatocellular carcinoma. Tumour Biol 39, 1010428317702649.
10. Chagas, CE, Bassoli, BK, de Souza, CA, et al. (2011) Folic acid supplementation during early hepatocarcinogenesis: cellular and molecular effects. Int J Cancer 129, 20732082.
11. Guariento, AH, Furtado, KS, de Conti, A, et al. (2014) Transcriptomic responses provide a new mechanistic basis for the chemopreventive effects of folic acid and tributyrin in rat liver carcinogenesis. Int J Cancer 135, 718.
12. Lee, D, Xu, IM, Chiu, DK, et al. (2017) Folate cycle enzyme MTHFD1L confers metabolic advantages in hepatocellular carcinoma. J Clin Invest 127, 18561872.
13. Cui, LH, Quan, ZY, Piao, JM, et al. (2016) Plasma folate and vitamin B12 levels in patients with hepatocellular carcinoma. Int J Mol Sci 17, 1032.
14. Wu, MY, Kuo, CS, Lin, CY, et al. (2009) Lymphocytic mitochondrial DNA deletions, biochemical folate status and hepatocellular carcinoma susceptibility in a case–control study. Br J Nutr 102, 715721.
15. Chang, SC, Goldstein, BY, Mu, L, et al. (2015) Plasma folate, vitamin B12, and homocysteine and cancers of the esophagus, stomach, and liver in a Chinese population. Nutr Cancer 67, 212223.
16. Welzel, TM, Katki, HA, Sakoda, LC, et al. (2007) Blood folate levels and risk of liver damage and hepatocellular carcinoma in a prospective high-risk cohort. Cancer Epidemiol Biomarkers Prev 16, 12791282.
17. Persson, EC, Schwartz, LM, Park, Y, et al. (2013) Alcohol consumption, folate intake, hepatocellular carcinoma, and liver disease mortality. Cancer Epidemiol Biomarkers Prev 22, 415421.
18. Peng, Y, Dong, B & Wang, Z (2016) Serum folate concentrations and all-cause, cardiovascular disease and cancer mortality: a cohort study based on 1999–2010 National Health and Nutrition Examination Survey (NHANES). Int J Cardiol 219, 136142.
19. Rossi, E, Hung, J, Beilby, JP, et al. (2006) Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia. Ann Epidemiol 16, 206212.
20. Wolpin, BM, Wei, EK, Ng, K, et al. (2008) Prediagnostic plasma folate and the risk of death in patients with colorectal cancer. J Clin Oncol 26, 32223228.
21. McEligot, AJ, Ziogas, A, Pfeiffer, CM, et al. (2015) The association between circulating total folate and folate vitamers with overall survival after postmenopausal breast cancer diagnosis. Nutr Cancer 67, 442448.
22. Yeh, CC, Goyal, A, Shen, J, et al. (2017) Global level of plasma DNA methylation is associated with overall survival in patients with hepatocellular carcinoma. Ann Surg Oncol 24, 37883795.
23. Crider, KS, Bailey, LB & Berry, RJ (2011) Folic acid food fortification-its history, effect, concerns, and future directions. Nutrients 3, 370384.
24. Midttun, O, Theofylaktopoulou, D, McCann, A, et al. (2017) Circulating concentrations of biomarkers and metabolites related to vitamin status, one-carbon and the kynurenine pathways in US, Nordic, Asian, and Australian populations. Am J Clin Nutr 105, 13141326.
25. Fang, AP, Chen, PY, Wang, XY, et al. (2018) Serum copper and zinc levels at diagnosis and hepatocellular carcinoma survival in the Guangdong Liver Cancer Cohort. Int J Cancer (Epublication ahead of print version 13 November 2018).
26. Benson, AB 3rd, Abrams, TA, Ben-Josef, E, et al. (2009) NCCN clinical practice guidelines in oncology: hepatobiliary cancers . J Natl Compr Canc Netw 7, 350391.
27. Pugh, RN, Murray-Lyon, IM, Dawson, JL, et al. (1973) Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 60, 646649.
28. Kamath, PS, Wiesner, RH, Malinchoc, M, et al. (2001) A model to predict survival in patients with end-stage liver disease. Hepatology 33, 464470.
29. Fedirko, V, Duarte-Salles, T, Bamia, C, et al. (2014) Prediagnostic circulating vitamin D levels and risk of hepatocellular carcinoma in European populations: a nested case–control study. Hepatology 60, 12221230.
30. Llovet, JM, Bru, C & Bruix, J (1999) Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 19, 329338.
31. Zhang, CX & Ho, SC (2009) Validity and reproducibility of a food frequency questionnaire among Chinese women in Guangdong province. Asia Pac J Clin Nutr 18, 240250.
32. Institute of Nutrition and Food Safety CC (2009) China Food Composition (Book 1), 2nd ed. Beijing: Peking University Medical Press.
33. Institute of Nutrition and Food Safety CC (2005) China Food Composition 2004. Beijing: Peking University Medical Press.
34. Willett, WC, Howe, GR & Kushi, LH (1997) Adjustment for total energy intake in epidemiologic studies. Am J Clin Nutr 65, 1220S1228S; discussion 1229S1231S.
35. Desquilbet, L & Mariotti, F (2010) Dose-response analyses using restricted cubic spline functions in public health research. Stat Med 29, 10371057.
36. Knol, MJ & VanderWeele, TJ (2012) Recommendations for presenting analyses of effect modification and interaction. Int J Epidemiol 41, 514520.
37. Hosmer, DW & Lemeshow, S (1992) Confidence interval estimation of interaction. Epidemiology 3, 452456.
38. Ito, Y, Wakai, K, Suzuki, K, et al. (2005) Lung cancer mortality and serum levels of carotenoids, retinol, tocopherols, and folic acid in men and women: a case–control study nested in the JACC Study. J Epidemiol 15, Suppl. 2, S140S149.
39. Lochhead, P, Nishihara, R, Qian, ZR, et al. (2015) Postdiagnostic intake of one-carbon nutrients and alcohol in relation to colorectal cancer survival. Am J Clin Nutr 102, 11341141.
40. Harris, HR, Bergkvist, L & Wolk, A (2012) Folate intake and breast cancer mortality in a cohort of Swedish women. Breast Cancer Res Treat 132, 243250.
41. Lee, TY, Chiang, EP, Shih, YT, et al. (2014) Lower serum folate is associated with development and invasiveness of gastric cancer. World J Gastroenterol 20, 1131311320.
42. Galvan-Portillo, MV, Onate-Ocana, LF, Perez-Perez, GI, et al. (2010) Dietary folate and vitamin B12 intake before diagnosis decreases gastric cancer mortality risk among susceptible MTHFR 677TT carriers. Nutrition 26, 201208.
43. Johansson, M, Fanidi, A, Muller, DC, et al. (2014) Circulating biomarkers of one-carbon metabolism in relation to renal cell carcinoma incidence and survival. J Natl Cancer Inst 106, dju327.
44. Dixon, SC, Ibiebele, TI, Protani, MM, et al. (2014) Dietary folate and related micronutrients, folate-metabolising genes, and ovarian cancer survival. Gynecol Oncol 132, 566572.
45. Ebbing, M, Bonaa, KH, Nygard, O, et al. (2009) Cancer incidence and mortality after treatment with folic acid and vitamin B12 . JAMA 302, 21192126.
46. Ulrich, CM & Potter, JD (2007) Folate and cancer—timing is everything. JAMA 297, 24082409.
47. Lee, JE, Willett, WC, Fuchs, CS, et al. (2011) Folate intake and risk of colorectal cancer and adenoma: modification by time. Am J Clin Nutr 93, 817825.
48. Kantor, ED, Rehm, CD, Du, M, et al. (2016) Trends in dietary supplement use among US adults from 1999–2012. JAMA 316, 14641474.
49. He, YN, Wang, Z, Zhao, LY, et al. (2017) Dietary intake of vitamins in Chinese population from 2010 to 2012. Ying Yang Xue Bao 39, 112115.
50. Wang, X, Fu, J, Li, Q, et al. (2016) Geographical and ethnic distributions of the MTHFR C677T, A1298C and MTRR A66G gene polymorphisms in Chinese populations: a meta-analysis. PLOS ONE 11, e0152414.
51. Medici, V & Halsted, CH (2013) Folate, alcohol, and liver disease. Mol Nutr Food Res 57, 596606.
52. Thuesen, BH, Husemoen, LL, Ovesen, L, et al. (2010) Lifestyle and genetic determinants of folate and vitamin B12 levels in a general adult population. Br J Nutr 103, 11951204.
53. El-Serag, HB (2011) Hepatocellular carcinoma. N Engl J Med 365, 11181127.
54. Sieghart, W, Pinter, M, Hucke, F, et al. (2013) Single determination of C-reactive protein at the time of diagnosis predicts long-term outcome of patients with hepatocellular carcinoma. Hepatology 57, 22242234.
55. Crider, KS, Yang, TP, Berry, RJ, et al. (2012) Folate and DNA methylation: a review of molecular mechanisms and the evidence for folate’s role. Adv Nutr 3, 2138.
56. Halsted, CH, Villanueva, JA, Devlin, AM, et al. (2002) Folate deficiency disturbs hepatic methionine metabolism and promotes liver injury in the ethanol-fed micropig. Proc Natl Acad Sci U S A 99, 1007210077.
57. Kuo, CS, Huang, CY, Kuo, HT, et al. (2014) Interrelationships among genetic C677T polymorphism of 5,10-methylenetetrahydrofolate reductase, biochemical folate status, and lymphocytic p53 oxidative damage in association with tumor malignancy and survivals of patients with hepatocellular carcinoma. Mol Nutr Food Res 58, 329342.
58. Lin, CC & Yin, MC (2007) B vitamins deficiency and decreased anti-oxidative state in patients with liver cancer. Eur J Nutr 46, 293299.
59. Kuo, CS, Lin, CY, Wu, MY, et al. (2008) Relationship between folate status and tumour progression in patients with hepatocellular carcinoma. Br J Nutr 100, 596602.
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