Association between genetic polymorphisms and platinum-induced ototoxicity in children
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Gabrielle Lui1,2, Naïm Bouazza1,2,3, Françoise Denoyelle4, Marion Moine1, Laurence Brugières5, Pascal Chastagner6, Nadège Corradini7, Natacha Entz-Werle8, Cécile Vérité9, Judith Landmanparker10, Hélène Sudour-Bonnange11, Marlène Pasquet12, Arnauld Verschuur13, Cécile Faure-Conter14, François Doz15,16,*, Jean-Marc Tréluyer1,2,3,17,* and On behalf of the SFCE (Société Française des Cancers de l’Enfant et l’Adolescent)
1University of Paris Descartes, EA 7323, Sorbonne Paris-Cité, France
2CIC-1419 Inserm, Cochin-Necker, Paris, France
3Clinical Research Unit of Paris Descartes Necker Cochin, AP-HP, Paris, France
4Department of Pediatric Otolaryngology, Necker Children’s Hospital, Paris, France
5Department of Children and Adolescents Oncology, Gustave Roussy, Villejuif, France
6Department of Pediatric Onco-Hematology, Children’s Hospital, Vandoeuvre Les Nancy, France
7Pediatric Oncology Department, Mother-Children Hospital, Nantes, France
8Pediatric Onco-Hematology Unit, CHU of Strasbourg, Strasbourg, France
9Pediatric Hematology Department, Bordeaux University Hospital, Bordeaux, France
10Sorbonne University, Department of Pediatric Hematology Oncology, APHP, Trousseau Hospital, Paris, France
11Pediatric Oncology Unit, Children, Adolescents and Young Adults Unit, Oscar Lambret Center, Lille, France
12Children’s Hospital, University Hospital of Toulouse, Toulouse, France
13Pediatric Oncology Department, La Timone Children’s Hospital, Marseilles, France
14Institute of Pediatric Hemato-Oncology, Lyon, France
15Oncology Center SIREDO, Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer, Curie Institute, Paris, France
16Paris Descartes University, Paris, France
17Department of Clinical Pharmacology, Cochin Hospital AP-HP, Paris, France
*These authors have contributed equally to this work
Gabrielle Lui, email: email@example.com
Keywords: platinum; pharmacogenetics; ototoxicity; children; cancer
Received: March 26, 2018 Accepted: June 25, 2018 Published: July 20, 2018
Platinum is extensively used in the treatment of several childhood cancers. However, ototoxicity is one of the most notable adverse effects, especially in children. Several studies suggest that genetics may predict its occurrence. Here, polymorphisms associated with platinum-induced ototoxicity were selected from the literature and were investigated in a pediatric population treated with platinum-based agents. In this retrospective study, patients treated with cisplatin and/or carboplatin were screened. The patients with pre- and post-treatment audiogram (Brock criteria) available were included. We selected polymorphisms that have previously been associated with cisplatin ototoxicity with a minor allele frequency ≥30%. Deletion of GSTM1 and GSTT1, rs1799735 (GSTM3), rs1695 (GSTP1), rs4880 (SOD2), rs2228001 (XPC), rs1799793 (XPD) and rs4788863 (SLC16A5) were investigated. Data of one hundred and six children matching the eligible criteria were analyzed. Thirty-three patients (31%) developed ototoxicity (with a Brock grade ≥2). The probability of hearing loss increased significantly in patients carrying the null genotype for GSTT1 (P = 0.03), A/A genotype at rs1695 (P = 0.01), and C/C genotype at rs1799793 (P = 0.008). We also showed an association of the cumulative doses of carboplatin with cisplatin ototoxicity (P <0.05).
To conclude, deletion of GSTT1, rs1695 and rs1799793 may constitute potential predictors of platinum-induced ototoxicity.
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