Different Prevalence of Drug Metabolism Gene Polymorphisms (GSTP and GSTT) in FA Patients Compared to a Normal Population.

Fanconi Anemia patients have an increased toxicity of drugs used in conditioning regimen (CT) for hematopoietic stem cell transplantation (HSCT), due to defective DNA repair processes. This observation has led to diminish the doses of drugs (such as cyclophosphamide and busulphan) and irradiation in the preparative regimen. We and others have reported that genetic polymorphisms, which interfere with metabolisms of drugs used in CT, are associated with toxicities after HSCT. In order to test the hypothesis that probably Fanconi patients have a difference in prevalence of pharmacogene polymorphisms, we have compared the samples of 49 Fanconi patients (median age of 6,2 years) with 107 samples of normal population of the same ethnic group. Polymerase chain reaction (PCR) and restriction-digestion protocols were used to identify most of the polymorphisms. We have selected pharmacogenes knonwn to interfere with the metabolisms of drugs used in the CT or GVHD prophylaxis. The following gene polymorphisms were analyzed: P450 cytochrome family [CYP2B6*2(C64T), *4(A785G), *5(C1459T), *6(G516T)]; glutathion-S-Transferases [GSTM1 (null), GSTT1(null), GSTP1(G313A)], Thiopurine-S-methyl transferase [TPMT *3B (G460A) and *3C (G238C)], Multiresistance-drug [MDR1 (C3435T)], Methylenetetrahydrofolate reductase [MTHFR (C677T, A1298C)], Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. All gene polymorphisms studied were found in the same frequency in FA as in normal controls, except polymorphisms of GSTP and GSTT. In fact, FA patients had a higher frequency of mutant alleles (AG or GG) of GSTP (86%; n=42) compared to 51% (n=55) in normal controls (p<0.001). GSTP polymorphisms are associated with reduced ability to detoxify chemotherapeutic agents thereby increasing the effective dose of the drug within the cell. It has also been associated with increased risk of breast, prostate, bladder and testicular cancer. We have also observed a decreased frequency of GSTT wild type (null; 8%, n=4) in FA patients compared to normal controls (25%, n=27) (p=0.01). In conclusion, this study shows that prevalence of GSTP and GSTT gene polymorphisms in FA is different from the normal population.