667C > T and 1298A > C polymorphisms of MTHFR do not predict response to methotrexate in patients with gestational trophoblastic neoplasia

ObjectiveApproximately one third of patients treated with methotrexate for gestational trophoblastic neoplasia (GTN) following a molar pregnancy are reported to develop resistance to methotrexate and need to change to different chemotherapeutic agents. Previous studies, in other clinical settings, have suggested that polymorphisms in key folate metabolising enzymes such as 5,10-methylenetetrahydrofolate reductase (MTHFR) influence both toxicity and efficacy of methotrexate. Our objective was to investigate the impact of two common functional MTHFR polymorphisms, 677C > T and 1298A > C, on the efficacy of methotrexate in women treated for GTN following a molar pregnancy.MethodsDNA from 121 women treated with methotrexate for GTN was genotyped for the 677C > T and 1298A > C polymorphisms using TaqMan SNP Genotyping Assays. In 64 cases these polymorphisms were also genotyped in the antecedent molar pregnancy, using DNA extracted from archival blocks of tissue. Response to methotrexate was evaluated with reference to serial human chorionic gonadotrophin (hCG) levels in patient serum.ResultsNo significant association was found between the genotype of the patient, or presence of the variant allele, and clinical response to methotrexate therapy for either the 677C > T or the 1298A > C SNP. No significant association was found between the genotypes of the molar tissue and response to methotrexate. In molar tissue there was a significant reduction in the expected number with the 677TT genotype suggesting the 677C > T SNP may identify a subgroup of molar pregnancies less likely to progress to GTN.ConclusionNeither the genotype for the 677C > T SNP or the 1298A > C SNP in MTHFR predict the therapeutic outcomes of women treated with single agent methotrexate for GTN.

► Polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene were investigated in patients treated with methotrexate for gestational trophoblastic neoplasia.
► The genotype of both the patients and their tumours was determined for the MTHFR polymorphisms 677C > T and 1298A > C.
► Response to methotrexate was not associated with the genotype of the patient for either the 677C > T or 1298A > C polymorphism.
► No association was found between the genotype of the tumour and response to methotrexate for either polymorphism.