Abstract

Fanconi anaemia (FA) patients are known to have a markedly increased toxicity of chemotherapeutic agents, due to impairment in various important cellular processes, such as DNA repair. This toxicity had led to several alterations in preparative regimens in the setting of haematopoietic stem cell transplantation (HSCT). Several polymorphisms in genes coding for metabolising enzymes and drug transporters have been described and are now being associated with predisposition to efficacy or toxicity to different drugs. We have driven the hypothesis that FA patients may have a different frequency of those gene polymorphisms. For this purpose we have studied two different FA populations and their controls. The following of genes were analyzed: P450 cytochrome [CYP2B6*2(C64T), *3(C777A), *4(A785G), *5(C1459T), *6(G516T)], Glutathione-S-Transferases [GSTM1 (null), GSTT1 (null), GSTP1 (A313G)], Methylenetetrahydrofolate reductase [MTHFR (C677T)] and Vitamin D receptor [VDR (ApaI, TaqI and BsmI)]. The first groupt consisted of 57 FA patients, from Saint Louis Hospital in Paris compared with 107 samples of a normal control population (healthy marrow donors) of the same ethnic group. The second group of patients consisted of 72 FA patients treated in the Hospital de Clinicas in Curitiba (Brazil) compared to a control population of 72 healthy blood donors matched to age, sex and ethnicity.

Results: in both groups, the frequency of CYP2B6 alleles, MTHFR, VDR and GSTP1 polymorphisms was not statistically different between patients and controls. For GSTT1, gene deletions were found in 5 (9%) of 57 FA patients and in 27 (25%) of the 107 controls from the first group, which revealed a significant difference (p=0.013). This result was also found in the second group of patients. In fact, GSTT1 null genotype was present in 8 (11%) of the 72 FA patients and in 19 (26%) of the normal controls (p=0.016). For GSTM1, the first group had no statistical difference in the frequency of gene deletions between FA patients and their controls. However, in the second group, GSTM1 null phenotype was found in 38 (53%) patients and in 26 (36%) controls (p=0.05). In conclusion, we found in two ethnically different groups, that FA patients may have a lower frequency of GSTT1 null genotype, compared to a normal population. GSTM1 null phenotype had a higher incidence in FA patients in the Brazilian group, but was not reproducible in the French group. This finding should be further analyzed to explain if it can be related to the disease itself and/or if it translates in increased toxicity of drugs in FA patients.

Author notes

Disclosure: No relevant conflicts of interest to declare.