Folate status and risk of relapse following allogeneic hematopoietic cell transplant for chronic myelogenous leukemia.

摘要

This dissertation includes (1) an overview of the vitamin folate, (2) a review of the risk factors associated with the development of chronic myelogenous leukemia (CML), (3) a review of polymorphisms of the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and the risk of leukemia, and finally, (4) a report on MTHFR polymorphisms and risk of relapse following hematopoietic cell transplant (HCT) for CML.; As an essential nutrient for nucleotide synthesis, folate is vital for rapidly replicating cells. Folate deficiency is known to increase the risk of double strand breaks due to uracil misincorporation into DNA, and has been linked to increased risk of certain cancers. MTHFR catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, directing intracellular folate towards homocysteine metabolism and away from nucleotide synthesis. Two common functional MTHFR polymorphisms, C677T and A1298C, are associated with reduced enzyme activity in vitro. We evaluated the association of these polymorphisms with the risk of relapse in a retrospective cohort study of 386 adult patients who underwent allogeneic HCT for CML. Information collected included exposure to factors related to folate status, such as the use the anti-folate medications methotrexate and trimethopfm-sulfamethoxazole, and multivitamin and folate supplementation pre- and post-transplant. Analysis of the MTHFR polymorphic sites individually showed a statistically non-significant trend towards decreased risk of relapse with at least one copy of the variant MTHFR 677 allele, whereas those with two variant MTHFR 1298 alleles had a statistically significant decreased risk of relapse. Individuals with the 677CC/1298CC genotype had the lowest risk of relapse after adjustment for year of transplant and the occurrence of graft-vs-host disease. Although this study population lacked sufficient variation to fully evaluate the effect of all folate related exposures, the effect of pre-transplant multivitamin or folate supplement use on relapse differed by MTHFR 677 genotype; decreasing the risk for individuals with at least one copy of the 677 variant T allele and increasing the risk for homozygous wildtype (677CC) individuals. Our findings suggest that individuals with the MTHFR 677CC/1298AA genotype might be at higher risk of relapse following HCT, and that the risk might be exacerbated by the use of supplemental folate.