title: A First Step toward Personalized Medicine in Osteosarcoma: Pharmacogenetics as Predictive Marker of Outcome after Chemotherapy-Based Treatment.
abstract: OBJECTIVE
  Overall survival in patients with osteosarcoma is only 60%. Poor response to chemotherapy is the dominant risk factor for poor survival. Pharmacogenetic research can offer possibilities to optimize treatment and improve outcome. We applied a pathway-based approach to evaluate the cumulative effect of genes involved in the metabolism of cisplatin and doxorubicin in relationship to clinical outcome.
  
  
  METHODS
  We included 126 patients with osteosarcoma. To comprehensively assess common genetic variation in the 54 genes selected, linkage disequilibrium (LD; r(2) = 0.8)-based tag-single nucleotide polymorphisms (SNP) strategy was used. A final set of 384 SNPs was typed using Illumina Beadarray platform. SNPs significantly associated with 5-year progression-free survival (PFS) were replicated in another 64 patients with osteosarcoma.
  
  
  RESULTS
  We identified five variants in FasL, MSH2, ABCC5, CASP3, and CYP3A4 that were associated with 5-year PFS. Risk stratification based on the combined effects of the risk alleles showed a significant improvement of 5-year PFS. Patients that carried no or only one risk allele had a 5-year PFS of 100% compared with a 5-year PFS of 84.4% for carriers of two or three risk alleles, 66.7% PFS if a patient carried four to five alleles, and a 5-year PFS of 41.8% for patients with >5 risk alleles (P < 0.001).
  
  
  CONCLUSIONS
  We identified several genes that showed association with PFS in patients with osteosarcoma. These pharmacogenetic risk factors might be useful to predict treatment outcome and to stratify patients immediately after diagnosis and offer the possibility to improve treatment and outcome.
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, the Netherlands. Melanie.Hagleitner@radboudumc.nl.
authors.forename: Melanie M
authors.initials: MM
authors.lastname: Hagleitner
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marieke J H
authors.initials: MJ
authors.lastname: Coenen
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, the Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Gelderblom
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Remco R
authors.initials: RR
authors.lastname: Makkinje
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Hanneke I
authors.initials: HI
authors.lastname: Vos
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Eveline S J M
authors.initials: ES
authors.lastname: de Bont
authors.affiliation: Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Winette T A
authors.initials: WT
authors.lastname: van der Graaf
authors.affiliation: Department of Orthopedic Surgery, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: H W Bart
authors.initials: HW
authors.lastname: Schreuder
authors.affiliation: Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Uta
authors.initials: U
authors.lastname: Flucke
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Frank N
authors.initials: FN
authors.lastname: van Leeuwen
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Hoogerbrugge
authors.affiliation: Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, the Netherlands.
authors.forename: Henk-Jan
authors.initials: HJ
authors.lastname: Guchelaar
authors.affiliation: Department of Pediatric Hematology and Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Dunja M W M
authors.initials: DM
authors.lastname: te Loo
mesh_terms: D000328:Adult; D000368:Aged; D053148:Caspase 3 / Q000235:genetics*; D002945:Cisplatin / Q000008:administration & dosage; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D018572:Disease-Free Survival; D004317:Doxorubicin / Q000008:administration & dosage; D053222:Fas Ligand Protein / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D012516:Osteosarcoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D057285:Precision Medicine; D011379:Prognosis; D016896:Treatment Outcome
chemical_list: D053148:Caspase 3; D002945:Cisplatin; D051544:Cytochrome P-450 CYP3A; D004317:Doxorubicin; D053222:Fas Ligand Protein; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D051718:MutS Homolog 2 Protein; C120809:ABCC5 protein, human; C505661:FASLG protein, human; C510163:CYP3A4 protein, human; C505407:CASP3 protein, human; C497172:MSH2 protein, human