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



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.



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.



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.
Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
S
S
Ruiz-Pinto
Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
G
G
Pita
Clinical Genetics Unit, University Clinic of Navarra (CUN), Pamplona, Spain.
A
A
Patiño-García
Department of Pediatric Hemato-Oncology, Hospital Universitario La Paz, Madrid, Spain.
P
P
García-Miguel
Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
J
J
Alonso
Department of Pediatric Hemato-Oncology, Hospital Universitario La Paz, Madrid, Spain.
A
A
Pérez-Martínez
Department of Pediatric Hemato-Oncology, Hospital Universitario La Paz, Madrid, Spain.
A
A
Sastre
Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain.
G
G
Gómez-Mariano
Department of Pediatrics, Division of Oncology and Hematology, Charité Universitaetsmedizin, Berlin, Germany.
A
A
Lissat
Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna, Italy.
K
K
Scotlandi
Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna, Italy.
M
M
Serra
Department of Pediatrics, Children's Cancer Research Institute, St Anna Kinderkrebsforschung e.V., Medical University, Vienna, Austria.
R
R
Ladenstein
Somatic Genetics Unit, Institut Curie, Paris, France.
E
E
Lapouble
Somatic Genetics Unit, Institut Curie, Paris, France.
G
G
Pierron
Division of Paediatric Haematology, Oncology and Stem Cell Transplantation, Department of Paediatrics and Adolescent Medicine, University Medical Centre, Aachen, Germany.
U
U
Kontny
Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna, Italy.
P
P
Picci
Department of Pediatrics, Children's Cancer Research Institute, St Anna Kinderkrebsforschung e.V., Medical University, Vienna, Austria.
H
H
Kovar
Inserm U830, Centre de Recherche, Institut Curie, Paris, France.
O
O
Delattre
Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain agonzalez@cnio.es.
A
A
González-Neira
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D065727:Cytochrome P-450 CYP2C8 / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
D018435:ATP Binding Cassette Transporter, Subfamily B; D065727:Cytochrome P-450 CYP2C8; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C513055:ABCB1 protein, human; C102029:ABCC6 protein, human; C450259:CYP2C8 protein, human
Ewing sarcoma; pathway-based approach; pharmacokinetic genes; polymorphisms; prognostic