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5,10-Methylenetetrahydrofolate Reductase Codon 677 and 1298 Polymorphisms
and Colon Cancer in African Americans and Whites
April 24, 2003

Reviewed by:

Katherine Wheeler
Rollins School of Public Health
Emory University

The Health Outcome

Colorectal cancer is the second leading type of cancer for black women and the third leading type for white women and all men.(1)  It also ranks third highest in cancer mortality for blacks and whites, men and women.(2) Five-year survival rates for patients in whom colorectal cancers are diagnosed are higher in whites (62 percent) than in blacks (52 percent).(3)

Epidemiologic studies have suggest an association between reduced folate intake, increased alcohol use and colon cancer.(4) Folate is important in the regulation of oncogene and tumor suppressor gene expression via DNA methylation.  High alcohol intake can reduce folate stores and may also play a role in colon cancer by inducing free radical damage to colon cells by way of acetaldehyde, the end product of alcohol metabolism.

The MTHFR enzyme converts 5-10-methylenetetrahydrofolate, a substrate of DNA synthesis, into 5-methyltetrahydrofolate, a key player in DNA methylation.(5) This study considers MTHFR C677T and A1298C polymorphisms and colon cancer among whites and African Americans. It also examines the gene-environment interactions with total daily folate intake and alcohol consumption.

The Finding

Keku et al. (2002) conducted a population-based case control study with 555 cases and 875 frequency-matched controls in North Carolina.  The distributions of the MTHFR 677 and 1298 alleles were consistent with similar populations elsewhere.  Total daily folate consumption <400ug was weakly associated with colon cancer (OR: 1.4, 95%CI: 1.0-2.0 African Americans; 1.6, 1.2-2.2 whites) adjusted for sampling fractions, age, sex, and total energy intake.  The authors found no crude association between alcohol consumption and colon cancer, nor any effect modification between alcohol consumption and low folate intake.  

For whites, the reduced-activity 1298 CC genotype slightly protective (0.5, 0.3-0.8).  This was not the case for the 677 TT genotype in either race.  In whites alone, a significant inverse association was found for colon cancer and the combined MTHFR genotype 1298 CC (mutant) + 677 CC (normal) (0.5, 0.2-0.8).

Both black and white subjects who consumed less than 400 ug of folate per day and had one or more normal alleles were more likely to have colon cancer (677 C: 1.4, 1.0-2.1 African Americans; 1.7, 1.3-2.3 whites; 1298 A: 1.4, 1.0-2.1 African Americans; 1.8, 1.3-2.4 whites). Whites with at least one normal allele, who did not use a folate dietary supplement were also more likely to be cases (677 C: 1.4, 1.1-2.0; 1298 A: 1.6, 1.2-2.1).  Whites who did not drink alcohol were less likely to have colon cancer if they had the mutated 1298 CC genotype (0.3, 0.2-0.7).(5)


Public Health Implications

Overall the literature is inconsistent regarding the association of MTHFR and colon cancer. (6-9) The present study argues that MTHFR polymorphisms, particularly A1298C, may play a protective role against disease in the presence of adequate folate intake.  However, the findings do more to confirm the importance of existing folate recommendations in the reduction of colon cancer risk than to make the case for MTHFR genotyping for more targeted interventions.  Furthermore, the importance of normal MTHFR activity has been well documented in the protection against other disorders, including neural tube defects.(10)  Further studies in different populations may help clarify the interaction of MTHFR and folate with respect to colon cancer.

References

  1. United States Cancer Statistics Working Group. United States Cancer Statistics: 1999 Incidence. Department of Health and Human Services, Atlanta, GA: CDC and NCI, 2002.
  2. NCI. United States Cancer Statistics: Fast Stats, Colon and Rectum Mortality, 1969-1999. Available at URL: http://www.seer.cancer.gov.
  3. American Cancer Society. Cancer Facts and Figures for African-Americans 2000-2001. ACS Inc., Atlanta, GA.
  4. Giovannucci E, Rimm EB, Ascherio A, et al. Alcohol, low-methionine, low-folate diets and risk of colon cancer in men. Natl Cancer Inst 1995; 87: 265-73.
  5. Keku T, Millikan R, Worley K, et al. 5-10-methylenetetrahydrofolate reductase codon 677 and 1298 polymorphisms and colon cancer in African Americans and whites. Cancer Epidemiol Biomarkers Prev 2002; 11: 1611-21.
  6. Ryan B, Molloy A, McManus R, et al. The methylenetetrahydrofolate reductase (MTHFR) gene in colorectal cancer: role in tumor development and significance of allelic loss in tumor progression. Int J Gastrointest Cancer 2001; 30 (3):105-11.
  7. Chen J, Ma J, Stampher M, Palomeque C, et al. Linkage disequilibrium between the 677C-T and 1298 A-C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer. Pharmacogenetics 2002; 12(4): 339-42.
  8. Delgado-Enciso I, Martinez-Garza S, Rojas-Martinez A, et al. 677T mutation of the MTHFR gene in adenomas and colorectal cancer in a population sample from the Northeastern Mexico, preliminary results. Rev Gastroenterol Mex 2001; 66(1): 32-7.
  9. Ulrich CM, Kampman E, Bigler J, et al. Lack of association between the C677T MTHFR polymorphism and colorectal hyperplastic polyps. Cancer Epidemiol Biomarkers Prev 2000; 9(4): 427-33.
  10. Botto L and Yang Q. MTHFR and congenital anomalies: A HuGE Review. Am J Epidemiol
    2000; 9: 862-877.
Last Updated August 25, 2004