title: 667C>T and 1298A>C polymorphisms of MTHFR do not predict response to methotrexate in patients with gestational trophoblastic neoplasia.
abstract: OBJECTIVE
  Approximately 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.
  
  
  METHODS
  DNA 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.
  
  
  RESULTS
  No 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.
  
  
  CONCLUSIONS
  Neither 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.
authors.affiliation: Institute of Reproductive & Developmental Biology, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 ONN, UK.
authors.forename: Lidia
authors.initials: L
authors.lastname: Lasecka
authors.forename: Peter H
authors.initials: PH
authors.lastname: Dixon
authors.forename: Mariam
authors.initials: M
authors.lastname: Molokhia
authors.forename: Nima
authors.initials: N
authors.lastname: Sharma
authors.forename: Annabel
authors.initials: A
authors.lastname: Schleh
authors.forename: Chiuhui Mary
authors.initials: CM
authors.lastname: Wang
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Steel
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Seckl
authors.forename: Philip M
authors.initials: PM
authors.lastname: Savage
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Fisher
mesh_terms: D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D005260:Female; D031901:Gestational Trophoblastic Disease / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D008727:Methotrexate / Q000627:therapeutic use*; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011247:Pregnancy; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D004273:DNA, Neoplasm; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate