Ulrich et al recently reported the association between a polymorphism of folate-metabolizing enzyme, methylenetetrahydrofolate reductase gene (MTHFR), 677C>T and risk of posttransplantation complications.1 The authors showed the significantly reduced oral mucositis index scores,2 and not significant but delayed hematologic recovery among patients with the TT genotype, compared with those with the CC genotype. They hypothesized that a modification of toxicity by MTHFRgenotype was due to methotrexate (MTX) use for posttransplantation prophylaxis for graft-versus-host disease (GVHD) because MTX is the antifolate drug whose common toxicity includes oral mucositis and hematologic complications.3 Previously, a similar finding that the grade 4 neutropenia (NCI-CTC criteria) following MTX including adjuvant-combined chemotherapy for breast cancer is more frequently observed among TT genotype was reported by Toffoli et al.4Although we basically agree with the concept that genetic variation ofMTHFR may predispose certain kinds of clinical/preclinical status as we have already reported,5 we are hesitant to view MTX as a modifier of the causal association between the genotype and toxicity.
In general, oral mucositis may occur in the conditioning regimens applied in their study even if they do not include MTX. As Ulrich et al mentioned, the most important point is the imbalances in folate pools in those with the TT genotype, which results in the decreased availability of folate for recovery by DNA synthesis. This means the MTHFR genotype represents a lesser ability to recover from the chemotherapy, not only by means of MTX. Their study did not examine the difference in toxicity for patients treated with MTX compared with those treated without MTX. In addition, no information on other important factors regarding oral mucositis, such as the pretransplantation condition of the oral cavity or HLA-matching status, was provided in this study. Because oral mucositis has been recognized as one of the prognostic factors for hematopoietic cell transplantation,6 a study exploring the predisposing factors would be important for clinical situations. We believe that these factors should be taken into account before drawing final conclusions and starting a dose-adjustment study of MTX for GVHD prophylaxis.
MTHFR polymorphism, DNA repair capacity, and methotrexate toxicity
Matsuo et al raise the question of whether the MTHFR677C>T polymorphism may affect oral mucositis in marrow-transplantation patients, independent of treatment with the antifolate drug methotrexate (MTX). The mechanism we proposed for explaining our findings1-1 involves (a) decreased provision of folate for nucleotide synthesis among patients with lower MTHFR activity (TT genotype), (b) a decreased ability for DNA repair, and therefore (c) greater damage and delayed healing of the oral mucosa among these patients. Naturally, one can expect similar effects in any situation involving the need for DNA repair. As we discussed, the conditioning regimens used in marrow-transplantation patients (cyclophosphamide / total body irradiation [Cy/TBI] or busulfan/cyclophosphamide [Bu/Cy]) by themselves induce oral mucositis.
But while the conditioning regimens result in oral mucositis, MTX has “additive” effects: when administered after transplantation for acute graft-versus-host disease (GVHD) prophylaxis, it can substantially increase the level of mucosal damage and delay healing. We have shown that, among marrow-transplant patients with Cy/TBI or Bu/Cy conditioning, MTX administration results in 45% of patients experiencing severe oral mucositis, compared with 8% of patients without MTX.1-2 Others have reported similar results.1-3
Thus a substantial amount of oral mucositis in the transplantation setting can be attributed to MTX administration, and an effect of theMTHFR polymorphism can be more easily observed in this situation of extreme folate depletion. One may expect a close link between a polymorphism affecting the balance of folate metabolites and the effect of an antifolate drug.
Our group,1-4 as well as others,1-5 1-6 has shown that the risk of colorectal neoplasia associated with the MTHFRpolymorphism varies by folate status, with an increased risk observed only among individuals with low folate intake or biomarkers indicating low folate status. Our findings on MTX toxicity, which induces a folate-depleted state, are consistent with this model of gene-nutrient interaction.
Matsuo et al were further concerned that information on the pretransplantation condition of the oral cavity or HLA-matching status was not considered. HLA-matching status was in our population equivalent to the type of conditioning regimen and was adjusted for in the statistical analyses. Oral mucositis scores before transplantation were extremely low (usually 0-1) and did not affect our results. Nevertheless, we agree with Matsuo et al that our findings need to be replicated in other populations, and the occurrence of GVHD needs to be evaluated before dose adjustment of MTX should be considered.
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