Influence of genetic polymorphisms on the risk of developing leukemia and on disease progression.

BACKGROUND

Recent studies have provided evidence that common genetic variations with low penetrance could account for a proportion of leukemia and could also influence disease outcome, although the results obtained are still controversial.

MATERIAL AND METHODS

We reviewed 54 recent reports focused on the contribution of genetic polymorphisms to the risk of developing leukemia and to disease progression. The polymorphisms of genes encoding drug-metabolising enzymes (CYP family, NQO1, GSTT1, GSTM1, GSTP1), enzymes involved in folate metabolism (MTHFR, TYMS, SHMT1, MTRR), and DNA repair enzymes (XPD, XPG, RAD51, XRCC1, XRCC3, CHEK2, ATM) were considered in the review.

RESULTS

There was a good agreement on the influence of NQO12 polymorphism and those of the enzymes involved in DNA repair with the increased risk of therapy-related leukemia/myelodysplastic syndrome. Most studies found a strong association between the polymorphisms MTHFR, C677T or A1298C, and NQO12 or *3 and the risk of acute lymphoblastic leukemia (ALL). In addition, most of the studies reported an association between GSTT1 deletions and an increased risk of de novo acute myeloid leukemia. In ALL, polymorphisms in the genes of folate metabolism are associated with poor prognosis, and the 3R3R TYMS polymorphism in particular is associated with methotrexate resistance.

CONCLUSION

The reports reviewed support the hypothesis that several low-penetrance genes with multiplicative effects together with dietary effects, ambient exposition, and individual immune system responses, may account for the risk of leukaemia.