Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome

Ann Oncol. 2016 Sep;27(9):1788-93. doi: 10.1093/annonc/mdw234. Epub 2016 Jun 10.

Abstract

Background: Despite the effectiveness of current treatment protocols for Ewing sarcoma (ES), many patients still experience relapse, and survival following recurrence is <15%. We aimed to identify genetic variants that predict treatment outcome in children diagnosed with ES.

Patients and methods: We carried out a pharmacogenetic study of 384 single-nucleotide polymorphisms (SNPs) in 24 key transport or metabolism genes relevant to drugs used to treat in pediatric patients (<30 years) with histologically confirmed ES. We studied the association of genotypes with tumor response and overall survival (OS) in a discovery cohort of 106 Spanish children, with replication in a second cohort of 389 pediatric patients from across Europe.

Results: We identified associations with OS (P < 0.05) for three SNPs in the Spanish cohort that were replicated in the European cohort. The strongest association observed was with rs7190447, located in the ATP-binding cassette subfamily C member 6 (ABCC6) gene [discovery: hazard ratio (HR) = 14.30, 95% confidence interval (CI) = 1.53-134, P = 0.020; replication: HR = 9.28, 95% CI = 2.20-39.2, P = 0.0024] and its correlated SNP rs7192303, which was predicted to have a plausible regulatory function. We also replicated associations with rs4148737 in the ATP-binding cassette subfamily B member 1 (ABCB1) gene (discovery: HR = 2.96, 95% CI = 1.08-8.10, P = 0.034; replication: HR = 1.60, 95% CI = 1.05-2.44, P = 0.029), which we have previously found to be associated with poorer OS in pediatric osteosarcoma patients, and rs11188147 in cytochrome P450 family 2 subfamily C member 8 gene (CYP2C8) (discovery : HR = 2.49, 95% CI = 1.06-5.87, P = 0.037; replication: HR = 1.77, 95% CI = 1.06-2.96, P = 0.030), an enzyme involved in the oxidative metabolism of the ES chemotherapeutic agents cyclophosphamide and ifosfamide. None of the associations with tumor response were replicated.

Conclusion: Using an integrated pathway-based approach, we identified polymorphisms in ABCC6, ABCB1 and CYP2C8 associated with OS. These associations were replicated in a large independent cohort, highlighting the importance of pharmacokinetic genes as prognostic markers in ES.

Keywords: Ewing sarcoma; pathway-based approach; pharmacokinetic genes; polymorphisms; prognostic.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • Adolescent
  • Adult
  • Child
  • Child, Preschool
  • Cytochrome P-450 CYP2C8 / genetics*
  • Female
  • Genetic Association Studies
  • Genotype
  • Humans
  • Infant
  • Male
  • Multidrug Resistance-Associated Proteins / genetics*
  • Neoplasm Recurrence, Local / drug therapy
  • Neoplasm Recurrence, Local / genetics
  • Neoplasm Recurrence, Local / pathology
  • Polymorphism, Single Nucleotide
  • Sarcoma, Ewing / drug therapy
  • Sarcoma, Ewing / genetics*
  • Sarcoma, Ewing / pathology
  • Survival Analysis
  • Treatment Outcome
  • Young Adult

Substances

  • ABCB1 protein, human
  • ABCC6 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • Multidrug Resistance-Associated Proteins
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8