title: Association of transcobalamin c. 776C>G with overall survival in patients with primary central nervous system lymphoma.
abstract: BACKGROUND
  Chemotherapy for primary central nervous system lymphoma (PCNSL) is based on methotrexate (MTX), which interferes with both nucleic acid synthesis and methionine metabolism. We have reported previously that genetic variants with influence on methionine metabolism are associated with MTX side effects, that is, the occurrence of white matter lesions as a sign of MTX neurotoxicity. Here, we investigated whether such variants are associated with MTX efficacy in terms of overall survival in MTX-treated PCNSL patients.
  
  
  METHODS
  We analysed seven genetic variants influencing methionine metabolism in 68 PCNSL patients treated with systemic and facultative intraventricular MTX-based polychemotherapy (Bonn protocol).
  
  
  RESULTS
  Median age at diagnosis was 59 years (range: 28-77), 32 patients were female. Younger age (Wald=8.9; P=0.003) and the wild-type C (CC) allele of the genotype transcobalamin c (Tc2). 776C>G (Wald=6.7; P=0.010) were associated with longer overall survival in a multivariate COX regression analysis.
  
  
  CONCLUSIONS
  This observation suggests that the missense variant Tc2. 776C>G influences both neurotoxicity and efficacy of MTX in the Bonn PCNSL protocol.
authors.affiliation: Department Neurology, University Hospital Bonn, Bonn, Germany. Michael.Linnebank@usz.ch
authors.forename: M
authors.initials: M
authors.lastname: Linnebank
authors.forename: S
authors.initials: S
authors.lastname: Moskau
authors.forename: A
authors.initials: A
authors.lastname: Kowoll
authors.forename: A
authors.initials: A
authors.lastname: Semmler
authors.forename: C
authors.initials: C
authors.lastname: Bangard
authors.forename: M
authors.initials: M
authors.lastname: Vogt-Schaden
authors.forename: G
authors.initials: G
authors.lastname: Egerer
authors.forename: G
authors.initials: G
authors.lastname: Schackert
authors.forename: H
authors.initials: H
authors.lastname: Reichmann
authors.forename: I G H
authors.initials: IG
authors.lastname: Schmidt-Wolf
authors.forename: H
authors.initials: H
authors.lastname: Pels
authors.forename: U
authors.initials: U
authors.lastname: Schlegel
mesh_terms: D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D005260:Female; D005838:Genotype; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics* / Q000401:mortality; D008297:Male; D008715:Methionine / Q000378:metabolism; D008727:Methotrexate / Q000009:adverse effects / Q000627:therapeutic use*; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D016019:Survival Analysis; D014155:Transcobalamins / Q000235:genetics*
chemical_list: D014155:Transcobalamins; D008715:Methionine; D008727:Methotrexate