title: Influence of the folate pathway and transporter polymorphisms on methotrexate treatment outcome in osteosarcoma.
abstract: OBJECTIVE
  Osteosarcoma is the most common primary bone malignancy that occurs mostly in adolescents. Treatment protocols usually include multiagent preoperative and postoperative chemotherapy based on methotrexate, cisplatin, doxorubicin and ifosfamide. Despite a favourable prognosis, there are considerable interindividual differences in treatment outcome. Genetic variability of enzymes involved in the metabolism and transport of methotrexate could contribute towards observed differences in response to chemotherapy. Our aim was to evaluate how polymorphisms in the folate pathway and transporter genes influence treatment outcome in osteosarcoma patients.
  
  
  METHODS
  In total, 44 osteosarcoma patients treated with methotrexate were genotyped for eleven polymorphisms in four folate pathway and five folate transporter genes. Cox regression was used in survival analysis. Logistic regression was used to assess the influence of polymorphisms on treatment efficacy and toxicity and nonparametric tests were used to determine the influence on serum methotrexate levels.
  
  
  RESULTS
  Polymorphic SLCO1B1 rs4149056 and rs11045879 alleles were associated with significantly higher serum methotrexate area under the curve (P=0.001 and 0.011, respectively). Carriers of at least one polymorphic SLCO1B1 rs4149056 and rs11045879 allele tended to have longer event-free survival compared with patients with two wild-type alleles [P=0.040, hazard ratio (HR)=0.26, 95% confidence interval (CI)=0.07-0.94; and P=0.034, HR=0.20, 95% CI=0.05-0.89, respectively]. Compared with the most common haplotype, carriers of both polymorphic alleles had significantly longer event-free survival (P=0.009, HR=0.27, 95% CI=0.10-0.72).
  
  
  CONCLUSIONS
  We have shown that SLCO1B1 polymorphisms influence methotrexate disposition and survival in methotrexate-treated osteosarcoma patients and therefore might serve as pharmacogenetic markers of treatment outcome.
authors.affiliation: aPharmacogenetics Laboratory, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana bInstitute of Oncology Ljubljana cOncology and Haematology Unit, University Children's Hospital, University Medical Centre, Ljubljana, Slovenia.
authors.forename: Katja
authors.initials: K
authors.lastname: Goričar
authors.forename: Viljem
authors.initials: V
authors.lastname: Kovač
authors.forename: Janez
authors.initials: J
authors.lastname: Jazbec
authors.forename: Branko
authors.initials: B
authors.lastname: Zakotnik
authors.forename: Janez
authors.initials: J
authors.lastname: Lamovec
authors.forename: Vita
authors.initials: V
authors.lastname: Dolžan
mesh_terms: D000293:Adolescent; D000328:Adult; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage*; D001859:Bone Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D002648:Child; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage*; D027361:Organic Anion Transporters / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D020641:Polymorphism, Single Nucleotide; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D005492:Folic Acid; D008727:Methotrexate