MTHFR polymorphisms and risk of chronic lymphocytic leukemia.

Folate availability is critical for DNA integrity, required for the transfer of methyl groups in the biosynthesis of thymidilate. Reduction of 5,10-methylenetetrahydrofolate, a donor for methylating dUMP to dTMP in DNA synthesis, to 5-methyltetrahydrofolate, the primary methyl donor for methionine synthesis, is catalyzed by 5,10-methylenetetrahydrofolate reductase (MTHFR). The MTHFR polymorphisms C677T and A1298C have been shown in some studies to alter the risk of a range of different malignancies. We evaluated the role of the C677T and A1298C polymorphisms on chronic lymphocytic leukemia (CLL) risk by genotyping 832 patients and 886 healthy controls. The odds ratio of CLL associated with 677CT and 677TT genotypes were 1.02 [95% confidence interval (95% CI), 0.83-1.24] and 0.90 (95% CI, 0.66-1.24), respectively. The odds ratio of CLL associated with 1298AC and 1298CC genotypes were 0.97 (95% CI, 0.79-1.18) and 0.88 (95% CI, 0.62-1.24), respectively. This data indicate that the MTHFR polymorphisms C677T and A1298C do not significantly contribute to an inherited genetic susceptibility to CLL.

[1]  Li Yu,et al.  [DNA methylation and cancer]. , 2005, Zhonghua nei ke za zhi.

[2]  P. M. Das,et al.  DNA methylation and cancer. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  K. Hemminki,et al.  Familial risk of lymphoproliferative tumors in families of patients with chronic lymphocytic leukemia: results from the Swedish Family-Cancer Database. , 2004, Blood.

[4]  G. Dianov,et al.  Repair of uracil residues closely spaced on the opposite strands of plasmid DNA results in double-strand break and deletion formation , 1991, Molecular and General Genetics MGG.

[5]  R. Houlston,et al.  Causation of chronic lymphocytic leukemia--insights from familial disease. , 2003, Leukemia research.

[6]  Cornelia M Ulrich,et al.  5,10-Methylenetetrahydrofolate reductase polymorphisms and leukemia risk: a HuGE minireview. , 2003, American journal of epidemiology.

[7]  U. Fallon.  Commentary: Colon cancer, folate and genetic status. , 2003, International journal of epidemiology.

[8]  S. Ogino,et al.  Genotype and haplotype distributions of MTHFR 677C>T and 1298A>C single nucleotide polymorphisms: a meta-analysis , 2003, Journal of Human Genetics.

[9]  M. Ehrlich,et al.  DNA methylation in cancer: too much, but also too little , 2002, Oncogene.

[10]  J. Peto,et al.  Genetics and the common cancers. , 2001, European journal of cancer.

[11]  Peter A. Jones,et al.  The Role of DNA Methylation in Mammalian Epigenetics , 2001, Science.

[12]  H. Blom,et al.  A second common variant in the methylenetetrahydrofolate reductase (MTHFR) gene and its relationship to MTHFR enzyme activity, homocysteine, and cardiovascular disease risk , 2001, Journal of Molecular Medicine.

[13]  G. M. Taylor,et al.  Methylenetetrahydrofolate reductase (MTHFR) polymorphisms and risk of molecularly defined subtypes of childhood acute leukemia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[14]  D. Syndercombe-Court,et al.  Role for CCG-trinucleotide repeats in the pathogenesis of chronic lymphocytic leukemia. , 2001, Blood.

[15]  Quanhe Yang,et al.  5,10-Methylenetetrahydrofolate reductase gene variants and congenital anomalies: a HuGE review. , 2000, American journal of epidemiology.

[16]  G. Morgan,et al.  Polymorphisms in the methylenetetrahydrofolate reductase gene are associated with susceptibility to acute leukemia in adults. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[17]  F. Gabreëls,et al.  A second common mutation in the methylenetetrahydrofolate reductase gene: an additional risk factor for neural-tube defects? , 1998, American journal of human genetics.

[18]  B. Ames,et al.  Folate deficiency causes uracil misincorporation into human DNA and chromosome breakage: implications for cancer and neuronal damage. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[19]  E. Rimm,et al.  A methylenetetrahydrofolate reductase polymorphism and the risk of colorectal cancer. , 1996, Cancer research.

[20]  N Risch,et al.  The Future of Genetic Studies of Complex Human Diseases , 1996, Science.

[21]  R. Matthews,et al.  A candidate genetic risk factor for vascular disease: a common mutation in methylenetetrahydrofolate reductase , 1995, Nature Genetics.

[22]  L. Alhonen,et al.  Genomic hypomethylation in human chronic lymphocytic leukemia. , 1992, Blood.

[23]  A. Riggs,et al.  DNA methylation and gene function. , 1980, Science.

[24]  J. Fleiss,et al.  A simple approximation for calculating sample sizes for comparing independent proportions. , 1980, Biometrics.

[25]  R. Grantham.  Amino Acid Difference Formula to Help Explain Protein Evolution , 1974, Science.