|Year : 2012 | Volume
| Issue : 1 | Page : 57-60
Folate and vitamin B12 deficiency is associated with colorectal cancer in Jordan
Mostafa I Waly1, Mostafa A Arafa2, Sahar B Jriesat3, Sunny A Sallam4, Ahmed Al-Kafajei5
1 Department of Food Science and Nutrition, College of Agricultural and Marine Sciences, Sultan Qaboos University, Muscat, Oman
2 Princess Al-Johara Al Ibrahim for Cancer Research, King Saud University, Saudi Arabia
3 Department of Data Management, Jordan Cancer Registry, Ministry of Health, Amman, Jordan
4 Department of Epidemiology, High Institute of Public Health, Alexandria University, Egypt
5 Department of Public Health, Faculty of Medicine, Jordan University for Science and Technology, Jordan
|Date of Submission||26-Jun-2011|
|Date of Acceptance||18-Jan-2012|
|Date of Web Publication||23-Feb-2012|
Mostafa I Waly
Department of Food Science and Nutrition, P.O. Box 34, Al-Koud-123, Sultan Qaboos University, Muscat
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Aim: This case-control study was aimed to evaluate the folate and vitamin B12 status among patients recently diagnosed with colorectal cancer (CRC), in Jordan. Materials and Methods: The study involved 220 recently diagnosed Jordanian CRC patients and 220 age- and gender-matched healthy controls. The dietary intake and biochemical assessment of folate and vitamin B12 were determined for all the study participants. Results: The CRC patients had lower daily intake and serum levels of both folate (189.28 ± 11.78 μg/day and 6.6 ± 1.3 μg/l, respectively) and vitamin B12 (1.09 ± 0.4 μg/day and 233.7 ± 17.9 pg/ml, respectively) as compared to their matched control groups (212.58 ± 13.18 μg/day and 16.2 ± 2.8 μg/l, respectively, for folate) and (2.49 ± 1.3 μg/day and 458.9 ± 30.9 pg/ml, respectively, for vitamin B12). Conclusion: The CRC Jordanian patients who participated in this study had a low status of folate and vitamin B12, and a well-established etiological factor for CRC.
Keywords: Colorectal cancer, folate, Jordan, vitamin B12
|How to cite this article:|
Waly MI, Arafa MA, Jriesat SB, Sallam SA, Al-Kafajei A. Folate and vitamin B12 deficiency is associated with colorectal cancer in Jordan. Int J Nutr Pharmacol Neurol Dis 2012;2:57-60
|How to cite this URL:|
Waly MI, Arafa MA, Jriesat SB, Sallam SA, Al-Kafajei A. Folate and vitamin B12 deficiency is associated with colorectal cancer in Jordan. Int J Nutr Pharmacol Neurol Dis [serial online] 2012 [cited 2019 Apr 24];2:57-60. Available from: http://www.ijnpnd.com/text.asp?2012/2/1/57/93127
| Introduction|| |
Risk factors for colorectal cancer (CRC) include hereditary, environmental factors, and dietary patterns. These represent the most controllable risk factors for CRC. 
Low intake of folate and vitamin B12 has been associated with an increased risk of CRC in animal and human clinical studies. It has been reported that there is approximately 40% reduction in the risk of colorectal adenomas and cancer in individuals with the highest dietary intake of folate and vitamin B12 as compared with those with the lowest intake of these nutrients. 
A large prospective study (the Nurses' Health Study, n=88,757) showed a 75% reduction in the risk of colorectal adenomas in women using multivitamins containing ≥ 400 μg folate for ≥ 15 years.  A significant dose-dependent inverse association between dietary folate intake and the risk of colorectal neoplasia was also reported. , Animal studies using chemical colon carcinogens and genetic knockout murine models also supported a casual relationship between folate and/ or vitamin B12 deficiency and colorectal cancer. ,
Daily dietary availability of folate and vitamin B12 is crucial for ensuring a threshold blood level of these nutrients to support the numerous metabolic pathways, including the methionine cycle that is regulated by a key regulatory enzyme, methionine synthase (MS) [Figure 1]. The ubiquitous enzyme MS requires 5-methyltetrahydrofolate (active form of folic acid) as a methyl donor and vitamin B12 as a cofactor.  This cycle is crucial for homocysteine (HCY) remethylation into methionine and for the biosynthesis of S-adenosylmethionine (SAM), the methyl donor, for more than 100 biological methylation reactions, including DNA methylation. 
|Figure 1: Simplified schematic of the folate-dependent methionine cycle. Homocysteine (HCY) is converted into methionine by methionine synthase (MS), which utilizes vitamin B12 as a cofactor and acquires a methyl group from the active form of folate, 5-methyltetrahydrofolate (5-CH3-THF), which is subsequently converted to tetrahydrofolate (THF). Methionine is further converted to S-adenosylmethionine(SAM), through the activity of methionine adenosyl transferase. SAM is the major methyl donor for all methyltransferases, which adds methyl groups to various acceptor molecules such as DNA, RNA, phospholipids, and proteins. SAM is then converted to S-adenosylhomocysteine (SAH), which is reversibly converted to HCY in a reaction catalyzed by SAH-hydrolase. Based on MS activity and the availability of folate and vitamin B12, HCY is re-methylated back to methionine, as mentioned earlier|
Click here to view
Under conditions of a low dietary supply of folate and vitamin B12, the methyl supply is low and consequently the MS activity is low, and this condition increases the risk of accumulation of HCY and low availability of SAM, concomitant with low DNA methylation, DNA hypomethylation. , Molecular genetic studies indicated that DNA hypomethylation is a leading cause of mutagenesis and abnormal expression of oncogenes, which have been implicated in different types of carcinogenesis, including colorectal cancer. ,,
In addition, normal DNA methylation is an important epigenetic determinant in gene expression and DNA stability, , and this gene-nutrient interaction (dietary involvement in DNA methylation) increases the risk of colorectal cancer among susceptible subjects (subjects with genetic polymorphisms in methylene tetrahydrofolate reductase (MTHFR) enzyme). ,,,
Although the impact of folate and vitamin B12 in the etiology of CRC is well-established in many western studies, there is scarce information about these studies in Jordan. Therefore, we decided to conduct this research to evaluate the status of folate and vitamin B12 among Jordanian subjects recently diagnosed with CRC, as compared to their matched healthy controls. The results of this study will shed light on the cultural and food consumption differences among CRC patients in Jordan as compared to the West.
| Materials and Methods|| |
This study was conducted between February 2008 and January 2009, at Al-Bashir Hospital, the central hospital for CRC referral, Ministry of Health, Hashemite Kingdom of Jordan. The study was approved by the Medical Research and Ethics Committee of the Ministry of Health in Jordan.
A case-control study approach was adopted to investigate the association between folate and vitamin B12 nutrients and risk of CRC. A total of 220 CRC cases (118 males and 102 females), recently diagnosed with colorectal adenocarcinoma, were recruited for this study. All cases were confirmed either by histopathology (95%) or by other methods including surgical examination, computed tomography scan/ultrasound, or x-ray (5%). Two hundred and twenty Jordanian healthy controls were recruited on a voluntary basis from the same hospital and frequently matched for age and gender distribution of the CRC cases. All controls were free of gastrointestinal diseases and other types of cancer. They voluntary signed a consent form specially designed for this study.
Each study participant was personally interviewed and the interview questionnaire included questions related to age, gender, residence, diet, and vitamin supplements. Height and weight were recorded for estimation of body mass index (BMI) based on the equation; BMI was equal to the adult weight in kilograms (kg) divided by the square of the adult height in meters (m 2 ), overweight was defined as a BMI of 25 - 30 kg/m 2 , while obesity was a BMI≥30 kg/m 2 . 
Dietary intake assessment
To overcome the problem of reverse causality, where cancer patients might change their dietary habits after the diagnosis, we included only the recently diagnosed cases in which diagnosis was confirmed 10 - 14 days prior to the dietary intake questionnaire. The retrospective dietary intake of folate and vitamin B12 were estimated using a semi-quantitative food frequency questionnaire (FFQ) that was tested for validity, reproducibility, and reliability.
The CRC cases and controls were asked to report the frequency of food consumption and portion size consumed, for each food item consumed within the previous 12 months. Also, all the study subjects were asked if they had changed their diet from the usual routine in the last 12 months. Daily intake of folate and vitamin B12 were analyzed using standard computer-assisted procedures (ESHA Research, The Food Processor, and version 10.2, Salem, OR, USA).
For blood sampling; 10 ml of venous blood was collected from the medial cubital vein. Blood samples were drawn by vein puncture into a plain tube. Following centrifugation, the serum was transferred to an Eppendorf tube and stored at -80°C prior to folate and vitamin B12 measurements at the Central Clinical Laboratory. The measurements were taken using an automated random-access immunoassay system from Siemens Medical Solutions Diagnostics, ADVIA Centaur (Bayer ADVIA Centaur) automated analyzer, the normal range for serum folate was defined as 3 - 20 μg/l, while for serum vitamin B12 the normal range was defined as 250 - 1250 pg/ml. ,
Data was expressed as the mean ± standard deviation (SD) of the different quantitative variables. Graph pad Prism Software (Version 5.0) was used to calculate Student's unpaired t-test and correlation coefficients for mean comparisons. A P value of <0.05 was considered statistically significant.
| Results|| |
The CRC cases and controls had comparable gender ratio and matched age (56.3 ± 12.3 years). Male subjects in both CRC and control groups had normal body mass index (BMI) values (23.9 ± 3.6 kg/m 2 and 25.3 ± 4.1 kg/ m 2 , respectively) with no statistically significant differences, P=0.390. Although 'overweight' was observed in the female subjects (27.3 ± 5.8 kg/m 2 for CRC patients, and 28.5 ± 7.05 kg/m 2 for controls), there were no statistically significant differences among the studied groups, P=0.47.
None of the study subjects had consumed any multivitamin supplements or food supplements that were rich in folate and/or vitamin B12. The mean daily intake of folate and vitamin B12 for CRC patients (189.28 ± 11.78 μg/day and 1.09 ± 0.4 μg/day, respectively) was significantly lower (P<0.05) than for the controls (212.58 ± 13.18 μg/day and 2.49 ± 1.3 μg/day, respectively), as presented in [Table 1].
[Table 1] demonstrates that the mean serum levels of folate and vitamin B12 among CRC patients were significantly lower (P<0.05) than in the control groups. For CRC patients, the mean serum level of folate measurement was (6.6 ± 1.3 μg/l) as compared to (16.2 ± 2.8 μg/l) for the controls. The same pattern was observed for serum vitamin B12 measurements, where the CRC patients had (233.7 ± 17.9 pg/ml) as compared to (458.9 ± 30.9 pg/ml) for the controls. It was found that serum folate and vitamin B12 were positively correlated with their dietary intake in both CRC patients and controls (r=0.11 and r=0.29, P<0.05, respectively).
|Table 1: Dietary intake and serum levels of folate and vitamin B12 among CRC patients and controls group |
Click here to view
| Discussion|| |
This study showed that the daily consumption of folic acid and vitamin B12 among the studied CRC patients was significantly lower than that in the control group and less than the recommended dietary allowances, the population reference intake value for adults being, 200 μg/day for folate and 2.4 μg/day for vitamin B12. 
The long-term low intake of folate and vitamin B12 predisposed the CRC patients to nutritional deficiencies of these two nutrients, as demonstrated by their low serum levels, when compared to the controls. The result of our study is in agreement with the western studies that have found a significant association between lower intake of folic acid and vitamin B12 with increased risk of colon and rectum cancer. ,,,, In addition, several studies have suggested that low dietary intake of folate and vitamin B12 might induce a low methylation capacity in human cells with a consequent reduction in DNA methylation, DNA hypomethylation, a well- known trigger of colon tumorgenesis in susceptible human subjects. ,,
In summary, the present data demonstrate an association between low dietary intakes of folate and vitamin B12 as well as low serum levels of these nutrients, among the studied Jordanian CRC patients. This study has some limitations and is subjected to bias as it is a hospital-based, case-control study, with a small sample size and memory issues related to recall of foods reported in the Food Frequency Questionnaire (FFQ).
| Acknowledgments|| |
The authors extend their deep appreciation and acknowledgment to the Director of the Jordan Cancer Registry, staff of the Jordanian Health facilities, and the Middle East Cancer Consortium, for their dedicated effort to complete this study.
| References|| |
|1.||Saini R. Role of probiotics in colorectal cancer. Int J Nutr Pharmacol Neurol Dis 2011;1:81-2. |
|2.||Kim YI. Folate and carcinogenesis: Evidence, mechanisms and implications. J Nutr Biochem 1990;10:66-88. |
|3.||Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, et al. Multivitamin use, folate and colon cancer in women in the Nurse's Health Study. Ann Intern Med 1998;129:517-24. |
|4.||Giovannucci E, Stampfer MJ, Colditz GA, Rimm EB, Trichopoulos D, Rosner BA, et al. Folate, methionine, and alcohol intake and risk of colorectal adenoma. J Nat Cancer Inst 1993;85:875-84. |
|5.||Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low methionie-low folate diets, and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265-73. |
|6.||Song J, Sohn KJ, Medline A, Ash C, Gallinger S, Kim YI. Chemopreventive effects of dietary folate on intestinal polyps in Apc+/-MSH2-/- mice. Cancer Res 2000;60:3191-9. |
|7.||Song J, Medline A, Mason JB, Gallinger S, Kim YI. Effects of dietary folate on intestinal tumorigenesis in the ApcMin mouse. Cancer Res 2000;60:5434-40. |
|8.||Shils ME. Modern Nutrition in Health and Disease. 10 th ed. USA: Lippincott Williams and Wilkins; 2006. p. 470-3. |
|9.||Cedar H. DNA methylation and gene activity. Cell 1988;53:3-4. |
|10.||Sibani S, Melnyk S, Pogribny IP, Wang W, Hiou-Tim F, Deng L, et al. Studies of methionine cycle intermediate (SAM, SAH), DNA methylation and the impact of folate deficiency on tumor numbers in min mice. Carcinogenesis 2002;23:61-5. |
|11.||Goelz SE, Vogelstein B, Hamilton SR, Feinberg AP. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science 1985;228:187-90. |
|12.||Tsai HC, Baylin SB. Cancer epigenetics: Linking basic biology to clinical medicine. Cell Res 2011;21:502-17. |
|13.||Kim YI. Methylenetetrahydrofolate reductase polymorphisms, folate and cancer risk: A paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev 2000;58:205-9. |
|14.||Haghighi MM, Radpour R, Mahmoudi T, Mohebbi SR, Vahedi M, Zali MR. Association between MTHFR polymorphism (C677T) with no familial colorectal cancer. Oncol Res 2009;18:57-63. |
|15.||Slattery ML, Schaffer D, Edwards SL, Ma KN, Potter JD. Are dietary factors involved in DNA methylation associated with colon cancer. Nutr Cancer 1997;28:52-62. |
|16.||Ma J, Stampfer MJ, Giovannucci E, Artigas C, Hunter DJ, Fuchs C, et al. Methylenetetrahydrofolate reductase and risk of colorectal cancer. Cancer Res 1997;57:1098-102. |
|17.||Slattery ML, Potter JD, Samowitz W, Schaffer D, Leppert M. Methylenetetrahydrofolate reductase, diet, and risk of colon cancer. Cancer Epidemiol Biomarkers Prev 1999;8:513-8. |
|18.||Ulrich CM, Kampman E, Bigler J, Schwartz SM, Chen C, Bostick R, et al. Colorectal adenomas and the C677T MTHFR polymorphism: Evidence for gene-environment interaction? Cancer Epidemiol Biomarkers Prev 1999;8:659-86. |
|19.||Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: Executive summary. Expert Panel on the Identification, Evaluation, and Treatment of Overweight in Adults. Am J Clin Nutr 1998;68:899-917. |
|20.||Kei S, Takahiro O, Yoshimasa K. Determination of vitamin B12 by ADVIA Centaur. J Anal Bio-Sci 2006;29:235-42. |
|21.||Ihara H, Watanabe T, Aoki Y, Nagamura Y, Totani M, Hashizume N. Dietary folate intake and serum folate status in Japanese women of childbearing age. J Anal Bio-Sci 2009;32:181-5. |
|22.||Food and Nutrition Board. Institute of Medicine. Dietary Refrence Intakes: Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin and Choline. Washington, DC: National Academy Press; 1998. p. 306-56. |
|23.||Giovannucci E, Rimm EB, Ascherio A, Stampfer MJ, Colditz GA, Willett WC. Alcohol, low-methionine, low-folate diet and risk of colon cancer in men. J Natl Cancer Inst 1995;87:265-73. |
|24.||de Vogel S, Dindore V, van Engeland M, Goldbohm RA, van den Brandt PA, Weijenberg MP. Dietary folate, methionine, riboflavin and vitamin B6 and risk of sporadic colorectal cancer. J Nutr 2008;138:2372-8. |
|25.||MacLennan R, Macrae F, Bain C, Battistutta D, Chapuis P, Gratten H, et al. Randomized trial of intake of fat, fiber and beta carotene to prevent colorectal adenoma. J Nat Cancer Inst 1995;87:1760-6. |
|26.||van den Brandt PA, Goldbohm RA, van't Veer P, Volovics A, Hermus RJ, Sturmans F. A large scale prospective cohort study on diet and cancer in The Netherlands. J Clin Epidemiol 1990;43:285-95. |
|27.||Potter JD. Nutrition and colorectal cancer. Cancer Causes Control 1996;7:127-46. |
|This article has been cited by|
||Folate/Vitamin B12 Supplementation Combats Oxidative Stress-Associated Carcinogenesis in a Rat Model of Colon Cancer
| ||Smitha Padmanabhan,Mostafa I. Waly,Varna Taranikanti,Nejib Guizani,Amanat Ali,Mohammad S. Rahman,Zaher Al-Attabi,Raya N. Al-Malky,Sultan N. M. Al-Maskari,Bader R. S. Al-Ruqaishi,Jianan Dong,Richard C. Deth |
| ||Nutrition and Cancer. 2018; : 1 |
|[Pubmed] | [DOI]|
||Colorectal Cancer in the Arab World - Screening Practices and Future Prospects
| ||Mostafa A Arafa,Karim Farhat |
| ||Asian Pacific Journal of Cancer Prevention. 2015; 16(17): 7425 |
|[Pubmed] | [DOI]|