Variants in Pharmacokinetic Genes Linked to Ewing Sarcoma Outcomes

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Polymorphisms in pharmacokinetic genes ABCC6, ABCB1, and CYP2C8 are linked with overall survival (OS) in pediatric patients with Ewing sarcoma.
Polymorphisms in pharmacokinetic genes ABCC6, ABCB1, and CYP2C8 are linked with overall survival (OS) in pediatric patients with Ewing sarcoma.

Polymorphisms in pharmacokinetic genes ABCC6, ABCB1, and CYP2C8 are linked with overall survival (OS) in pediatric patients with Ewing sarcoma, a study published in Annals of Oncology has shown.1

Although current treatment protocols for Ewing sarcoma are effective, many patients relapse, and post-recurrence survival is less than 15%. Researchers attempted to identify genetic variants that predict treatment outcome in pediatric patients with Ewing sarcoma.

Investigators analyzed 384 single nucleotide polymorphisms in 24 key transport or metabolism genes connected to drugs that are used to treat Ewing sarcoma patients who are younger than 30. The association of genotypes with tumor response and overall survival in a discovery cohort of 106 Spanish children was assessed, with replication in a second cohort of 389 children from across Europe.

Both the Spanish study and European replication results showed links with OS for 3 single nucleotide polymorphisms. The strongest association observed was with rs7190447, located in the ABCC6 gene (discovery: hazard ratio, 14.30; 95% CI, 1.53-134; P = .020; replication: hazard ratio, 9.28; 95% CI, 2.20-39.2; P = .0024).

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An association with OS was also observed for rs4148737 in the ABCB1 gene (discovery: hazard ratio, 2.96, 95% CI, 1.08-8.10; P = .034; replication: hazard ratio, 1.60; 95% CI, 1.05-2.44; P = .029). This single nucleotide polymorphism has previously been linked to poorer OS in patients with pediatric osteosarcoma.

The third genetic variant detected was rs11188147 in CYP2C8, an enzyme involved in the metabolism of cyclophosphamide and ifosfamide, alkylating agents used for the treatment of Ewing sarcoma (discovery: hazard ratio, 2.49; 95% CI, 1.06-5.87; P = .037; replication: hazard ratio, 1.77; 95% CI, 1.06-2.96; P = .030).

No associations with tumor response identified in the Spanish cohort were replicated in the European cohort.

Reference

  1. Ruiz-Pinto S, Pita G, Patino-Garcia A, García-Miguel P, Alonso J, Pérez-Martínez A, et al. Identification of genetic variants in pharmacokinetic genes associated with Ewing Sarcoma treatment outcome [published online ahead of print June 10, 2016]. Ann Oncol. doi: 10.1093/annonc/mdw234.

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