S Ruiz-Pinto1, G Pita1, A Patiño-García2, P García-Miguel3, J Alonso4, A Pérez-Martínez3, A Sastre3, G Gómez-Mariano4, A Lissat5, K Scotlandi6, M Serra6, R Ladenstein7, E Lapouble8, G Pierron8, U Kontny9, P Picci6, H Kovar7, O Delattre10, A González-Neira11. 1. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. 2. Clinical Genetics Unit, University Clinic of Navarra (CUN), Pamplona, Spain. 3. Department of Pediatric Hemato-Oncology, Hospital Universitario La Paz, Madrid, Spain. 4. Pediatric Solid Tumor Laboratory, Human Genetic Department, Research Institute of Rare Diseases, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. 5. Department of Pediatrics, Division of Oncology and Hematology, Charité Universitaetsmedizin, Berlin, Germany. 6. Experimental Oncology Laboratory, Istituto Ortopedico Rizzoli, Bologna, Italy. 7. Department of Pediatrics, Children's Cancer Research Institute, St Anna Kinderkrebsforschung e.V., Medical University, Vienna, Austria. 8. Somatic Genetics Unit, Institut Curie, Paris, France. 9. Division of Paediatric Haematology, Oncology and Stem Cell Transplantation, Department of Paediatrics and Adolescent Medicine, University Medical Centre, Aachen, Germany. 10. Inserm U830, Centre de Recherche, Institut Curie, Paris, France. 11. Human Genotyping Unit-CeGen, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain agonzalez@cnio.es.
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.
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 osteosarcomapatients, 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.
Authors: Roelof Koster; Orestis A Panagiotou; William A Wheeler; Eric Karlins; Julie M Gastier-Foster; Silvia Regina Caminada de Toledo; Antonio S Petrilli; Adrienne M Flanagan; Roberto Tirabosco; Irene L Andrulis; Jay S Wunder; Nalan Gokgoz; Ana Patiño-Garcia; Fernando Lecanda; Massimo Serra; Claudia Hattinger; Piero Picci; Katia Scotlandi; David M Thomas; Mandy L Ballinger; Richard Gorlick; Donald A Barkauskas; Logan G Spector; Margaret Tucker; D Hicks Belynda; Meredith Yeager; Robert N Hoover; Sholom Wacholder; Stephen J Chanock; Sharon A Savage; Lisa Mirabello Journal: Int J Cancer Date: 2017-12-23 Impact factor: 7.396