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Vitamin B12 may play a preventive role in esophageal precancerous lesions: a case–control study based on markers in blood and 3-day duplicate diet samples

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Abstract

Purpose

It is hypothesized that vitamin B12 may prevent tumor initiation during the early stage of carcinogenesis such as esophageal precancerous lesions (EPL), whereas an excessive level may promote tumor progression during the later stages of carcinogenesis. This study aimed to determine the role of vitamin B12 in EPL by detecting vitamin B12-related markers in both blood and diet.

Methods

This case–control study based on 3-day duplicated diet samples was conducted in a high-risk area of Huai'an, China. A 100 EPL cases and 100 healthy controls matched by gender, age (± 2 years) and villages were included. Dietary intake of vitamin B12 and cobalt, plasma cobalt level, the serum levels of vitamin B12 and transcobalamin II (TC II) were quantitatively analyzed.

Results

Dietary vitamin B12 intake (p for trend = 0.384) and plasma cobalt level (p for trend = 0.253) were not associated with EPL risk, but high dietary cobalt intake (p for trend = 0.034), increased serum levels of vitamin B12 (p for trend = 0.036) and TC II (p for trend < 0.001) were significantly associated with the reduced EPL risk. However, the significant negative association between dietary cobalt intake, plasma cobalt level or serum vitamin B12 level and EPL was only found in female or male subjects.

Conclusion

Excellent transport capability of bio-active vitamin B12 in vivo and adequate levels of vitamin B12 and cobalt may play preventive roles in EPL. Additionally, the association between vitamin B12, cobalt and the risk of EPL may vary in different genders.

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Availability of data and material

All data generated or analyzed during this study are included.

Code availability

The technical appendix and statistical procedure are available from the corresponding author.

Abbreviations

BMI:

Body mass index

CI:

Confidence: interval

DHQ:

Dietary history questionnaire

EAC:

Esophageal adenocarcinoma

EC:

Esophageal cancer

EDETPEC:

Early Diagnosis and Early Treatment Project of Esophageal Cancer

ELISA:

Enzyme-linked immunosorbent assay

EPL:

Esophageal precancerous lesion

ESCC:

Esophageal squamous cell carcinoma

FFQ:

Food frequency questionnaire

MTHFR:

5,10-Methylenetetrahydrofolate reductase

OD:

Optical density

OR:

Odds ratio

TC II:

Transcobalamin II

References

  1. Pan D, Su M, Zhang T, Miao C, Fu L, Yang L, Song G, Raine PJ, Wang S, Sun G (2019) A distinct epidemiologic pattern of precancerous lesions of esophageal squamous cell carcinoma in a high-risk Area of Huai’an, Jiangsu Province. China Cancer Prev Res 12(7):449–462. https://doi.org/10.1158/1940-6207.capr-18-0462

    Article  Google Scholar 

  2. Rustgi AK, El-Serag HB (2014) Esophageal carcinoma. N Engl J Med 371(26):2499

    Article  PubMed  Google Scholar 

  3. Zhang T, Pan D, Su M, Fu LM, Miao CY, Yan QY, Wang J, Yang LG, Wang SK, Sun GJ (2018) Determination of dietary nitrite in patients with esophageal pre-cancerous lesion and normal people: a duplicate diet study. Food Addit Contam A 35(12):2298–2308. https://doi.org/10.1080/19440049.2018.1546906

    Article  CAS  Google Scholar 

  4. Wang S, Pan D, Zhang T, Su M, Sun G, Wei J, Guo Z, Wang K, Song G, Yan Q (2020) Corn flour intake, aflatoxin B1 exposure, and risk of esophageal precancerous lesions in a high-risk area of huai’an, china: a case-control study. Toxins 12(5):299. https://doi.org/10.3390/toxins12050299

    Article  CAS  PubMed Central  Google Scholar 

  5. Wang S, Pan D, Su M, Huang G, Sun G (2020) Moderately high folate level may offset the effects of aberrant DNA methylation of P16 and P53 genes in esophageal squamous cell carcinoma and precancerous lesions. Genes & Nutrition 15(1):18. https://doi.org/10.1186/s12263-020-00677-x

    Article  CAS  Google Scholar 

  6. Abnet CC, Arnold M, Wei WQ (2018) Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 154(2):360–373. https://doi.org/10.1053/j.gastro.2017.08.023

    Article  PubMed  Google Scholar 

  7. Qiang Y, Li Q, Xin Y, Fang X, Tian Y, Ma J, Wang J, Wang Q, Zhang R, Wang J, Wang F (2018) Intake of dietary one-carbon metabolism-related b vitamins and the risk of esophageal cancer: a dose-response meta-analysis. Nutrients 10(7):835

    Article  PubMed Central  Google Scholar 

  8. Xiao Q, Freedman ND, Ren J, Hollenbeck AR, Abnet CC, Park Y (2014) Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. Br J Cancer 110(5):1328–1333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Matejcic M, de Batlle J, Ricci C, Biessy C, Perrier F, Huybrechts I, Weiderpass E, Boutron-Ruault MC, Cadeau C, His M, Cox DG, Boeing H, Fortner RT, Kaaks R, Lagiou P, Trichopoulou A, Benetou V, Tumino R, Panico S, Sieri S, Palli D, Ricceri F, Bueno-de-Mesquita HB, Skeie G, Amiano P, Sanchez MJ, Chirlaque MD, Barricarte A, Quiros JR, Buckland G, van Gils CH, Peeters PH, Key TJ, Riboli E, Gylling B, Zeleniuch-Jacquotte A, Gunter MJ, Romieu I, Chajes V (2017) Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort. Int J Cancer 140(6):1246–1259. https://doi.org/10.1002/ijc.30536

    Article  CAS  PubMed  Google Scholar 

  10. Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P (2005) Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: a prospective study. Int J Cancer 113(5):819–824. https://doi.org/10.1002/ijc.20646

    Article  CAS  PubMed  Google Scholar 

  11. Price AJ, Travis RC, Appleby PN, Albanes D, Barricarte Gurrea A, Bjorge T, Bueno-de-Mesquita HB, Chen C, Donovan J, Gislefoss R, Goodman G, Gunter M, Hamdy FC, Johansson M, King IB, Kuhn T, Mannisto S, Martin RM, Meyer K, Neal DE, Neuhouser ML, Nygard O, Stattin P, Tell GS, Trichopoulou A, Tumino R, Ueland PM, Ulvik A, de Vogel S, Vollset SE, Weinstein SJ, Key TJ, Allen NE, Endogenous Hormones NB, Prostate Cancer Collaborative G (2016) Circulating folate and vitamin B12 and risk of prostate cancer: a collaborative analysis of individual participant data from six cohorts including 6875 cases and 8104 controls. Eur Urol 70(6):941–951. https://doi.org/10.1016/j.eururo.2016.03.029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. de Vogel S, Meyer K, Fredriksen A, Ulvik A, Ueland PM, Nygard O, Vollset SE, Tell GS, Tretli S, Bjorge T (2013) Serum folate and vitamin B12 concentrations in relation to prostate cancer risk–a Norwegian population-based nested case-control study of 3000 cases and 3000 controls within the JANUS cohort. Int J Epidemiol 42(1):201–210. https://doi.org/10.1093/ije/dys199

    Article  PubMed  Google Scholar 

  13. Pan D, Su M, Huang G, Luo P, Zhang T, Fu L, Wei J, Wang S, Sun G (2019) MTHFR C677T genetic polymorphism in combination with serum vitamin B2, B12 and aberrant DNA methylation of P16 and P53 genes in esophageal squamous cell carcinoma and esophageal precancerous lesions: a case-control study. Cancer Cell Int 19:288. https://doi.org/10.1186/s12935-019-1012-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Arendt JFH, Sorensen HT, Horsfall LJ, Petersen I (2019) Elevated vitamin B12 levels and cancer risk in UK primary care: a THIN database cohort study. Cancer Epidemiol Biomarkers Prev 28(4):814–821. https://doi.org/10.1158/1055-9965.EPI-17-1136

    Article  CAS  PubMed  Google Scholar 

  15. Araghi SO, Kiefte-de Jong JC, van Dijk SC, Swart KMA, van Laarhoven HW, van Schoor NM, de Groot LCPGM, Lemmens V, Stricker BH, Uitterlinden AG, van der Velde N (2019) Folic acid and vitamin B12 supplementation and the risk of cancer: long-term follow-up of the B vitamins for the prevention of osteoporotic fractures (B-PROOF) trial. Cancer Epidemiol Biomarkers Prev 28(2):275–282. https://doi.org/10.1158/1055-9965.EPI-17-1198

    Article  CAS  Google Scholar 

  16. Collin SM, Metcalfe C, Refsum H, Lewis SJ, Zuccolo L, Smith GD, Chen L, Harris R, Davis M, Marsden G, Johnston C, Lane JA, Ebbing M, Bonaa KH, Nygard O, Ueland PM, Grau MV, Baron JA, Donovan JL, Neal DE, Hamdy FC, Smith AD, Martin RM (2010) Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 19(6):1632–1642. https://doi.org/10.1158/1055-9965.EPI-10-0180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lajous M, Willett W, Lazcano-Ponce E, Sanchez-Zamorano LM, Hernandez-Avila M, Romieu I (2006) Folate, vitamin B12 and vitamin B6 intake and the risk of breast cancer among Mexican women. Am J Epidemiol 161(11):S14–S14

    Google Scholar 

  18. Zhang SM, Cook NR, Albert CM, Gaziano JM, Buring JE, Manson JE (2008) Effect of combined folic acid, vitamin B6, and vitamin B12 on cancer risk in women: a randomized trial. JAMA 300(17):2012–2021. https://doi.org/10.1001/jama.2008.555

    Article  PubMed  PubMed Central  Google Scholar 

  19. van den Donk M, Pellis L, Crott JW, van Engeland M, Friederich P, Nagengast FM, van Bergeijk JD, de Boer SY, Mason JB, Kok FJ, Keijer J, Kampman E (2007) Folic acid and vitamin B-12 supplementation does not favorably influence uracil incorporation and promoter methylation in rectal mucosa DNA of subjects with previous colorectal adenomas. The Journal of nutrition 137(9):2114–2120. https://doi.org/10.1093/jn/137.9.2114

    Article  PubMed  Google Scholar 

  20. Kok DE, Dhonukshe-Rutten RA, Lute C, Heil SG, Uitterlinden AG, van der Velde N, van Meurs JB, van Schoor NM, Hooiveld GJ, de Groot LC, Kampman E, Steegenga WT (2015) The effects of long-term daily folic acid and vitamin B12 supplementation on genome-wide DNA methylation in elderly subjects. Clin Epigenet 7:121. https://doi.org/10.1186/s13148-015-0154-5

    Article  CAS  Google Scholar 

  21. Brasky TM, White E, Chen CL (2017) Long-term, supplemental, one-carbon metabolism-related vitamin B use in relation to lung cancer risk in the vitamins and lifestyle (VITAL) cohort. J Clin Oncol 35(30):3440–3448. https://doi.org/10.1200/JCO.2017.72.7735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bonetti F, Brombo G, Zuliani G (2017) Chapter 15 – The Role of B Group Vitamins and Choline in Cognition and Brain Aging. Nutr Funct Foods Healthy Aging

  23. Kohlmeier M (2003) Vitamin B12. In. pp 603–613. https://doi.org/10.1016/B978-012417762-8.50085-5

  24. Allen RH, Stabler SP (2008) Identification and quantitation of cobalamin and cobalamin analogues in human feces. Am J Clin Nutr 87(5):1324–1335. https://doi.org/10.1093/ajcn/87.5.1324

    Article  CAS  PubMed  Google Scholar 

  25. Albert MJ, Mathan VI, Baker SJ (1980) Vitamin B12 synthesis by human small intestinal bacteria. Nature 283(5749):781–782. https://doi.org/10.1038/283781a0

    Article  CAS  PubMed  Google Scholar 

  26. Carmel R, Herbert V (1969) Deficiency of vitamin B12-binding alpha globulin in two brothers. Blood 33(1):1–12

    Article  CAS  PubMed  Google Scholar 

  27. Oberley MJ, Yang DT (2013) Laboratory testing for cobalamin deficiency in megaloblastic anemia. Am J Hematol 88(6):522–526. https://doi.org/10.1002/ajh.23421

    Article  CAS  PubMed  Google Scholar 

  28. Unal S, Rupar T, Yetgin S, Yarali N, Dursun A, Gursel T, Cetin M (2015) Transcobalamin II deficiency in four cases with novel mutations. Turk J Hematol 32(4):317–322. https://doi.org/10.4274/tjh.2014.0154

    Article  CAS  Google Scholar 

  29. Meyers PA, Carmel R (1984) Hereditary transcobalamin-II deficiency with subnormal serum cobalamin levels. Pediatrics 74(5):866–871

    CAS  PubMed  Google Scholar 

  30. Schiff M, de Baulny HO, Bard G, Barlogis V, Hamel C, Moat SJ, Odent S, Shortland G, Touati G, Giraudier S (2010) Should transcobalamin deficiency be treated aggressively? J Inherit Metab Dis 33(3):223–229. https://doi.org/10.1007/s10545-010-9074-x

    Article  PubMed  Google Scholar 

  31. Pan D, Wang SK, Su M, Wei J, Wang K, Luo PF, Smith JD, Ma GG, Sun GJ (2020) Roles of drinking and diet in the U-shaped relationship between smoking and BMI in middle-aged and elderly Chinese rural adults. Sci Rep-Uk 10 (1)

  32. Chatthanawaree W (2011) Biomarkers of cobalamin (vitamin B12) deficiency and its application. J Nutr Health Aging 15(3):227–231. https://doi.org/10.1007/s12603-010-0280-x

    Article  CAS  PubMed  Google Scholar 

  33. Cui XY, Wang B, Wu YM, Xie LY, Tang QY, Shen XH (2019) Vitamin B12 status of vegetarians in Shanghai. Chin J Clin Nutr 27(2):107–112

    Google Scholar 

  34. Bailey LB (2004) Folate and vitamin B-12 recommended intakes and status in the United States. Nutr Rev 62(6):S14–S20. https://doi.org/10.1111/j.1753-4887.2004.tb00065.x

    Article  PubMed  Google Scholar 

  35. Coleman HG, Xie SH, Lagergren J (2018) The epidemiology of esophageal adenocarcinoma. Gastroenterology 154(2):390–405. https://doi.org/10.1053/j.gastro.2017.07.046

    Article  PubMed  Google Scholar 

  36. Mayne ST, Risch HA, Dubrow R, Chow WH, Gammon MD, Vaughan TL, Farrow DC, Schoenberg JB, Stanford JL, Ahsan H, West AB, Rotterdam H, Blot WJ, Fraumeni JF (2001) Nutrient intake and risk of subtypes of esophageal and gastric cancer. Cancer Epidemiol Biomarkers Prev 10(10):1055–1062

    CAS  PubMed  Google Scholar 

  37. O’Doherty MG, Cantwell MM, Murray LJ, Anderson LA, Abnet CC, Grp FS (2011) Dietary fat and meat intakes and risk of reflux esophagitis, Barrett’s esophagus and esophageal adenocarcinoma. Int J Cancer 129(6):1493–1502. https://doi.org/10.1002/ijc.26108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Jorhem L, Sundström B (1993) Levels of lead, cadmium, zinc, copper, nickel, chromium, manganese, and cobalt in foods on the swedish market, 1983–1990. J Food Compos Anal 6(3):223–241. https://doi.org/10.1006/jfca.1993.1025

    Article  CAS  Google Scholar 

  39. Xie LY, Wang B, Ma K, Mao XX, Shen XH (2018) The content of vitmain B12 in Chinese common foods. Food Nutr China 24(2):73–76

    Google Scholar 

  40. Rose M (1976) Letter: Vitamin-B12 deficiency in Asian immigrants. Lancet 2(7987):681. https://doi.org/10.1016/s0140-6736(76)92482-x

    Article  CAS  PubMed  Google Scholar 

  41. No author. Contribution Of the Microflora Of the Small-Intestine To the Vitamin-B12 Nutriture Of Man (1980). Nutrition Reviews 38 (8):274–275

  42. Ma Z, Li W (2019) How and why men and women differ in their microbiomes: medical ecology and network analyses of the microgenderome. Adv Sci 6(23):1902054. https://doi.org/10.1002/advs.201902054

    Article  CAS  Google Scholar 

  43. Combs GF (2012) Chapter 17 - Vitamin B12. In: Combs GF (ed) The Vitamins, 4th edn. Academic Press, San Diego, pp 377–394. https://doi.org/10.1016/B978-0-12-381980-2.00017-7

    Chapter  Google Scholar 

  44. De Stefani E, Ronco A, Mendilaharsu M, Deneo-Pellegrini H (1999) Diet and risk of cancer of the upper aerodigestive tract–II. Nutr Oral Oncol 35(1):22–26. https://doi.org/10.1016/s1368-8375(98)00061-x

    Article  Google Scholar 

  45. Jessri M, Rashidkhani B, Hajizadeh B, Jessri M, Gotay C (2011) Macronutrients, vitamins and minerals intake and risk of esophageal squamous cell carcinoma: a case-control study in Iran. Nutr J 10:137. https://doi.org/10.1186/1475-2891-10-137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Tuyns AJ, Riboli E, Doornbos G, Pequignot G (1987) Diet and esophageal cancer in Calvados (France). Nutr Cancer 9(2–3):81–92. https://doi.org/10.1080/01635588709513915

    Article  CAS  PubMed  Google Scholar 

  47. Ibiebele TI, Hughes MC, Pandeya N, Zhao Z, Montgomery G, Hayward N, Green AC, Whiteman DC, Webb PM, Study of Digestive H, Australian Cancer S (2011) High intake of folate from food sources is associated with reduced risk of esophageal cancer in an Australian population. J Nutr 141(2):274–283. https://doi.org/10.3945/jn.110.131235

    Article  CAS  Google Scholar 

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Acknowledgments

We thank all the participants, researchers and collaborators who were involved in the study for their efforts and contribution. Thanks to Dr. Ying Zhang for providing technical guidance on methods for ICP-MS. Thanks also to Mr Rob Unwin for proof reading. This research was supported by the National Natural Science Foundation of China (No. 81673147), Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX20_0063) and the Danone Dietary Nutrition Research and Education Foundation (DIC2020-08). The funding unit had no role in the whole study including study design, collection of data, and analysis of results and composition of the manuscript.

Funding

This research was supported by the National Natural Science Foundation of China (No. 81673147), Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJCX20_0063) and the Danone Dietary Nutrition Research and Education Foundation (DIC2020-08). The funding unit had no role in the whole study including study design, collection of data, analysis of results, and composition of the manuscript.

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Author notes

  1. Da Pan and Shaokang Wang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Environmental Medicine and Engineering of Ministry of Education, and Department of Nutrition and Food Hygiene, School of Public Health, Southeast University, Nanjing, 210009, People’s Republic of China

    Da Pan, Shaokang Wang, Guiju Sun, Xiaopan Zhu, Mahsa Ghahvechi Chaeipeima, Ziqi Guo, Niannian Wang, Ziyu Zhang & Mengjing Cui

  2. Huai’an District Center for Disease Control and Prevention, Huai’an, 223200, People’s Republic of China

    Ming Su

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  1. Da Pan
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Contributions

DP, SW, and GS designed research; DP, MS, XZ, MGC, ZG, NW, and ZZ conducted research; SW, MS, MC, and GS provided essential materials; DP analyzed data; DP wrote paper; SW had primary responsibility for final content. All authors read and approved the final manuscript.

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Correspondence to Shaokang Wang.

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The study was approved by the Institutional Review Board of Southeast University Zhongda Hospital, in accordance with the Declaration of Helsinki.

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Written informed consent was obtained from each subject.

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Pan, D., Wang, S., Su, M. et al. Vitamin B12 may play a preventive role in esophageal precancerous lesions: a case–control study based on markers in blood and 3-day duplicate diet samples. Eur J Nutr 60, 3375–3386 (2021). https://doi.org/10.1007/s00394-021-02516-0

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