Gene Polymorphisms and Altered Risk of Adult Acute Lymphocytic Leukemia

Martyn T. Smith
University of California, Berkeley
P30ES01896

Background: Although the clinical and pathological aspects of leukemia are well known, little is understood about the genes that influence susceptibility to this complex disease. Certain gene polymorphisms have been shown to alter the risk of development of leukemia and these variations can interact with diet, other environmental exposures, and individual immune function to be major determinants of susceptibility. This researcher has previously reported polymorphisms in a folate metabolizing gene with a decreased risk of acute adult lymphocytic leukemia (ALL). The research hypothesis is that the protective effect is due to an increase in the flux of folate compounds available for DNA synthesis and subsequent reductions of uracil in the DNA. Accumulation of uracil in DNA and its subsequent removal during excision repair processes can result in DNA double strand breaks which are necessary for chromosomal translocations and deletions.

Advance: Polymorphisms in methionine synthase (MS), cytosolic serine hydroxymethyltransferase (SHMT), and a double or triple 28-base pair tandem repeat in the promoter region of thymidylate synthase (TS) were studied and all were found to reduce ALL risk dramatically. When individuals had both the SHMT polymorphisms and the triple repeats in TS or the MS and SHMT polymorphisms the ALL risk was even further reduced.

Implications: This research illustrates an association between changes in folate metabolic pathways which affect TS and lymphocytic leukemia risk that may underscore the importance of compromised DNA fidelity and insufficient folate intake in the development of ALL. DNA integrity is dependent on the bioavailability of deoxynucleotides, particularly in cells with high replication rates such as those found in the hematopoetic system and epithelium. Moreover, low intake of folic acid and other factors such as vitamins B2, B6, and B12 may increase ALL risk in persons with high risk genotypes. A combination of unfavorable genotypes, diet, and vitamin B intake and balance may conceivably be the key factor in susceptibility to ALL. Continued research may lead to dietary and nutritional modifications to decrease the risk of genetically susceptible individuals.

Citation: Skibola CF, Smith MT, Hubbard A, Shane B, Roberts AC, Law GR, Rollinson S, Roman E, Cartwright RA, and Morgan GJ. Polymorphisms in the thymidylate synthase and hydroxymethyltransferase genes and risk of adult acute lymphocytic leukemia. Blood 2002; 99, 10:3786-3791.